EA011439B1 - Fused pyrimidine derivatives and compositions thereof as cxcr3 receptor modulators, useful in prevention and treatment and of inflammatory and immunoregulatory disorders and diseases - Google Patents

Abstract

Compounds are provided having the formula:wherein variables R, R, R, R, R, A, A, L, Q, X and subscript n as described herein. The subject compounds are useful for treatment of inflammatory and immune conditions and diseases. Compositions and methods of treatment using the subject compounds are also provided. For example, the subject methods are useful for treatment of inflammatory and immune disorders and disease such as multiple sclerosis, rheumatoid arthritis, psoriasis, and inflammatory bowel disease.

Description

The present invention relates to new modulators of CXCK3 receptors, compositions comprising new compounds, and methods of their use for the treatment of, for example, inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis and atherosclerosis.

Chemokines are chemotactic cytokines that are produced by a wide variety of cells to attract macrophages, T lymphocytes, eosinophilic granulocytes, basophilic leukocytes and neutrophilic granulocytes to inflammation sites (for a review of the properties, see publications 8, 11, Sucte, 3: 165-183 (1991) ; 8sya11 e! A1., Sigg. Θρίη 1ttypo1., 6: 865-873 (1994); Mithryu, Keu. 1type., 12: 593-633 (1994)). In addition to stimulating chemotasis, chemokines can selectively cause other changes in sensitive cells, including changes in the shape of cells, a temporary increase in the concentration of intracellular free calcium ions ([Ca ²⁺ ]) ₁ , granule exocytosis, and an increase in holistic functional activity (t! Edlp irgyedi), the formation of bioactive lipids (e.g., leukotrienes) and respiratory burst associated with the activation of white blood cells. Thus, chemokines are mechanisms for the early activation of the response to inflammation, causing release of the inflammatory mediator, chemotaxis and transudation to sites of infection or inflammation.

There are four classes of chemokines: CXC (a), CC ((c), C (y), and CX ₃ C (5), which differ depending on whether the first two cysteines are separated by a single amino acid (C-X-C) whether they are adjacent (C-C), whether there is a lack of a cysteine pair (C) or whether they are separated by three amino acids (CX ₃ C) α-chemokines, such as interleukin-8 (1L-8), a protein with stimulation activity the growth of melanoma (te1apoto \\ 111 5Ti1a! ogu asyuu ptot! es - MC8A) and the factor obtained from stromal cells (51gota1 se11 bebuy Gas! og - 8ΌΕ-1) are chemotactic, mainly at the same time, for neurophilic granulocytes and lymphocytes, while (β-chemokines such as ΚΑΝΤΕ8, M1P1α, ΜΙΡ-1β, monocytic chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin (eo! aht), are chemotoxic for macrophages, T lymphocytes, eosinophils and basophils (Iepde! A1, No. 11ige. 381: 661-666 (1996)). With chemokine lymphotaxin it is specific for lymphocytes (Ke1peg e! A1,. , 266: 1395-1399 (1994)), while CX ₃ C chemokine fractalkine shows specificity for lymphocytes and monocytes (Wahap e! A1., No. 1ge. 385: 640-644 (1997)).

Chemokines bind specific cell surface receptors belonging to the C-protein-linked family of seven transmembrane domains (for a review of the properties, see Nogik, Tgepbz Ryatt. 8sk, 15: 159-165 (1994)), which are called “chemokine receptors”. Chemokine receptors, when bound to ligands with an affinity for them, convert the intracellular signal through the associated heterotrimeric C protein, leading to a rapid increase in intracellular calcium concentration. There are at least twelve human chemokine receptors that bind β-chemokines with a subsequent characteristic pattern or are sensitive to (β-chemokines: CCK1 (or SCK-1 or CC-SKK-1) ΜΙΡ-1α, M1P-1c, MCP-3 , ΚΑΝΤΕ8 (Vep-Vatgisy, e! A1., 1. Vu1. Syet., 270: 22123-22128 (1995); No. oe e! A1., Ce11, 72: 415-425 (1993)); CCK2A and SSK2V (or SKK-2A / SKK-2A or SS-SKK-2A / SS-SKK2A ''), MCP-1, MCP-3, MCP-4; SSC3 (or SKK-3 or SS-SKK-3) eotaxin, KAKTE8, MCP; (RopaSh, e! a1., 1. Exp. Meb., 183: 2437-2448 (1996)); SSK4 (or SKK-4 or SS-SKK-4) TAKS, MOS (1t1 e ! a1., 1. Vu1 Syet., 273: 17 64-17 68 (1998)); SSK5 (or SKK-5 or SS-SKK-5) M1 P-1a, KAKHTE 8. M1P-f (8apzop, e! A1., Vyusyetschyu, 35: 3362-3367 (1996)); CCK6 M1P-3a (Sgeauez, e! A1., 1. Exp. Meb., 186: 837-844 (1997)); ССК7 М1Р-3в and 6Сшше (Сатре11 е! А1., 1. Се11 Вю1, 141: 1053-1059 (1998)); ССК8 Ι-309, ННУ8 уМ1Р-1, ННУ-8 уМ1Р -P, ISU uMSS-Ι (Papa ^ Y, e! A1., 1. Vyu1. Siet., 274: 21569-21574 (1999)); SSK9 TESK (/; 11y11oz.e! A1., 1. 1ttypo1, 162: 5671-5675 (1999)), Ό6 M1P-1v, KA # TE8 and MCP-3 (№ b3, e! A1., 1. Vu1. Siet., 272: 32078-32083 (1997)) and KAKTE8 antigen of the Duffy blood group, MCP-1 (Syaibyip, e! A1., 1. Vu1. Siet., 269: 7835-7838 (1994)).

Chemokine receptors, such as CCK1, CCK2, CCK2A, CCK2B, CCK3, CCK4, CCK5, CCK6, CCK7, CCK8, CCK9, SKXK1, SKKK2, SKKK3, SKKK4, SKKK5, SKKh ₃ SK1 and mediator inflammation are considered important and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.

CXC3 chemokine receptor is expressed mainly in T lymphocytes, and its functional activity can be quantified by an increase in the content of cytosolic calcium or chemotaxis. Previously, the receptor was called CPK9 or SKK-L2. Among chemokine receptors, it is distinguished by its chromosomal location, since it is localized in Xc. | 13.

The identified ligands, which are selective and have a high affinity for it, are CXC chemokines, 1P10, M1C and 1TAC.

The highly selective expression of CXC3 makes it an ideal target for intervention to

- 1 011439 interruption of the abnormal direction of migration of T lymphocytes. Clinical indications for this intervention are autoimmune diseases carried out by T lymphocytes, such as multiple sclerosis, rheumatoid arthritis and type I diabetes. Abnormal T lymphocyte infiltration also occurs in psoriasis and other pathogenic inflammatory conditions of the skin, although diseases may not be true autoimmune disorders. Then, a common sign of cutaneous immunopathology is an increase in the regulation of ΙΡ-10 expression in keratinocytes. Therefore, inhibition of CXSC3 may be useful to reduce the rejection function during organ transplantation. Ectopic expression of CXC3.3 in some tumors, especially in the subsets of malignant B cell malignancies, shows that selective CXC33 inhibitors will be relevant in tumor immunotherapy, especially for weakening metastasis.

In view of the clinical importance of CXC3, compounds that modulate CXC3 function can be used to develop new therapeutic agents. Such compounds are provided in the present invention.

The present invention provides compounds suitable for the treatment or prophylaxis of certain inflammatory and immunoregulatory disorders and diseases, including asthma, psoriasis, inflammatory bowel diseases and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and multiple sclerosis. In accordance with one aspect, provided are compounds of general formula (I)

where A ¹ and A ⁴ independently represent C (K ^b ) or Ν; O is selected from the group comprising a bond, (C1-C8) alkylene, (C2-C8) heteroalkylene, -C (O) -, -OC (O) -, -CH2CO-, -CH28O- and -CH28O2-; B represents a bond or (C1-C5) alkylene; X represents —CH 2 -, 8 O 2 or —C (O) -; K ^{a is} selected from the group consisting of -OK ', = O, = ΝΚ', = Ν-ΟΚ ', -ΝΚ'Κ, -8K', -halogen, -8ίΚ 'KK''', -OS (O) K ', -С (О) К', -СО2К ', СОХК'К, -ОС (О) 1 \ 1К'К, -К1КС (О) К', -ХК ¹ -С (О) ХКК ''', -K1KS (O) 2K ', -ΝΙΙ-ΟΝΙΚ) N11. -ΝΚ'ϋ (ΝΗ2) = ΝΗ, -ΝΗ-ϋ (ΝΗ2) = ΝΚ ', -8 (О) К', -8 (О) 2К ', -8 (О) 2ЫК'К, -ϋΝ and - ΝΟ <K ^{b is} selected from the group including -OK ', = O, = ΝΚ', = Ν · ΌΚ '-ΝΚ'Κ, -8K', -halogen, -81K'KK ''', -OC (O) K ', -C (O) K', -CO2K ', -CO1 \ 1K'K, -OC (O) 1 \ 1K'K, -1 \ 1KS (O) K', -1 \ 1K'-C (O)] \ 1KK ''', -1 \ 1KS (O) ₂ K', -ΝΗ-ϋ (ΝΗ ₂ ) = ΝΗ, -NΚ'С (NΗ ₂ ) = NΗ, -ΝΗ-С (ΝΗ ₂ ) = ΝΚ ', -K', -8 (O) K ', -8 (O) ₂ K', -8 (Ο) ₂ NΚ'Κ, -ϋΝ and -ОО ₂ ; the subscript η is 0, 1, 2, or 3; each of K ′, K, and K ″ ″ independently is H, unsubstituted (C1-C8) alkyl, heteroalkyl, unsubstituted aryl or substituted aryl; K ¹ represents heteroaryl or aryl; K ^{2 is} selected from the group consisting of hydrogen, halogen, (C1-C10) alkyl, (C2-C10) heteroalkyl, hetero (C1-C10) cycloalkyl, (C1C10) alkylaryl and (C2-C10) heteroalkylaryl or, optionally, K ² together with b they can form a 5-, 6-, 7 or 8-membered ring containing from 1 to 3 heteroatoms selected from the group consisting of Ν, O and 8 atoms; K ^{3 is} absent or selected from the group consisting of —H, —CIKK ⁷ , 8 (O) tK ⁵ , -8 (O) tY (K ⁸ ) K ⁹ , -8 (O) .. L '(1C) C11; ! /, -Ы (К ⁸ ) 8О2К ⁵ , -Ν (ΚΧΊΙ; Κ

or, optionally, K ³ together with K ² can form a 4-, 5-, 6-, 7- or 8-membered ring containing from 1 to 3 heteroatoms selected from the group consisting of Ν, O and 8 atoms; K ^{4 is} selected from the group consisting of (C1-C20) alkyl, (C2-C20) heteroalkyl, heteroaryl, aryl, heteroaryl (C1-C6) alkyl, heteroaryl (C2-C6) heteroalkyl, aryl (C1-C6) alkyl and aryl (C2-C6) heteroalkyl; K ^{5 is} selected from the group consisting of (C1-C8) alkyl, (C2-C8) heteroalkyl, aryl and heteroaryl; K ⁶ and K ⁷ independently represent hydrogen, (C1-C8) alkyl or (C2-C8) heteroalkyl; By ⁸ is hydrogen, (C1-C8) alkyl, (C2-C8) heteroalkyl, heteroaryl or aryl, R ⁹ represents _(C1-C8) alkyl; K ¹⁰ represents aryl; Ζ represents CH or Ν; X ¹ represents a bond, (C ₁ -C ₆ ) alkylene or (C ₁ -C ₆ ) heteroalkylene; Υ ¹ represents (C1-C6) alkylene; and the subscript m is 0, 1, or 2.

In accordance with another aspect, the invention provides compounds of formula (III)

- 2 011439

Β ⁴ ' ^α Υ κ ³

-OS (O) K ', -C (O) K',

-ΝΗ- ^ ΝΗ ₂ ) = ΝΗ, -ΝΒ '€ (ΝΗ ₂ ) = ΝΗ, -ΝΗIII where A ¹ and A ⁴ independently represent C (K ^b ) or Ν; O is selected from the group comprising a bond, (C ₁ -C ₈ ) alkylene, (C ₂ -C ₈ ) heteroalkylene, -C (O) -, -OC (O) -, -CH ₂ CO-, -CH ₂ 8O - and -CH ₂ 8O ₂ -; each of and Υ independently represents a carbon atom or a heteroatom, and and Υ joined together form

5- or 6-membered cycloalkyl or cycloheteroalkyl ring, wherein the 5- or 6-membered ring is unsubstituted or substituted with halogen, ΝΗ ₂ , NO ₂ , (C ₁ -C ₂₀ ) alkyl, (C ₁ -C ₂₀ ) heteroalkyl, heteroaryl , aryl, heteroaryl (C ₁ -C ₆ ) alkyl, heteroaryl (C ₂ -C ₆ ) heteroalkyl, aryl (C ₂ -C ₆ ) alkyl and aryl (C ₂ -C ₆ ) heteroalkyl; X represents —CH ₂ -, 8O ₂ or —C (O) -; K ^{a is} selected from the group consisting of OK ', = O, = NΒ', = N-OK ', -ΝΒ ¹ ", -8K', -halogen, -81K'KK ''', -OC (O) K' , -C (O) K ', -CO2K', -CO1 \ 1B'K, OC (O) NΒK, ^ KC (O) K ', ^' - CCO ^ 'K''', ^ C ( O) 2K ', C (NΗ2) = NΒ', -8 (O) K ', -8 (O) 2K', -8 (O) 2NΒ'K, -ΟΝ and ^ O2; K ^L is selected from the group consisting -tuples ', = O, = NΒ', = N-OK '^' R, -8K ', -halogen, -81K'KK''', OC (O) NΒ'K , ^ КС (О) К ', ^' - ССО ^ 'К''', ^ С (О) 2К ', С (NΗ ₂ ) = NΒ', -8 (О) К ', -8 (О) ₂ K '-8 (O) ₂ NΒ'K, -6Ν and ^ O ₂ ; the subscript η is 0, 1, 2, or 3; each K ′, K and K ″ ″ independently is H, unsubstituted (C2-C8) alkyl, heteroalkyl, unsubstituted aryl or substituted aryl; K ¹ represents heteroaryl or aryl; K ^{3 is} absent or selected from the group consisting of —H, —SC ⁶ K ⁷ , 8 (O) mK ⁵ , -8 (O) m ^ K ⁸ ) K ⁹ , -8 (O) m ^ K ⁸ ) CH2K ⁶ , - ^ K ⁸ ) 8О2К ⁵ , -ОС (О) К ', -С (О) К', -СО2К ', -СОХК'К. -ΝΗ- ^ ΝΗ ₂ ) = ΝΗ, -ΝΒΌ (ΝΗ ₂ ) = ΝΗ, -νη-

K ^{4 is} selected from the group consisting of (C2-C20) alkyl, (C2-C20) heteroalkyl, heteroaryl, aryl, heteroaryl (C2-C6) alkyl, heteroaryl (C2-C6) heteroalkyl, aryl (C2-C6) alkyl and aryl (C2-C6) heteroalkyl; K ⁵ is selected from the group consisting of _(C2-C8) alkyl, (C ₂ -C ₈₎ heteroalkyl, aryl and heteroaryl; K ⁶ and K ⁷ independently represent hydrogen, (C2-C8) alkyl or (C2-C8) heteroalkyl; K ⁸ represents hydrogen, (C2-C ₈ ) alkyl, (C ₂ -C ₈ ) heteroalkyl, heteroaryl or aryl, K ⁹ represents (C ₂ -C ₈ ) alkyl; and K ¹⁰ represents aryl.

The compounds of the invention include pharmaceutically acceptable salts, solvates or prodrugs.

In accordance with another aspect, the present invention provides pharmaceutical compositions comprising a compound of formula (I) or (III) and a pharmaceutically acceptable excipient or carrier.

In accordance with another aspect, the present invention provides methods of treating or preventing an inflammatory or immune disease or disorder, comprising administering to a subject in need of such treatment or prophylaxis a therapeutically effective amount of a compound of formula (I) or (III). Preferred subjects for the methods of the present invention are mammals, for example humans.

The present invention also provides methods of treating or preventing a condition or disorder carried out by the CXCK3 chemokine receptor, said methods comprising administering to a subject in need of such treatment or prophylaxis a therapeutically effective amount of a compound of formula (I) or (III).

The present invention also provides methods for modulating SCX3, comprising contacting a cell with a compound of formula (I) or (III).

The present invention also provides methods for modulating CXC3, comprising contacting CXC3 protein with a compound of formula (I) or (III).

In addition, the present invention provides methods for producing compounds of formula (I) or (III).

In FIG. 1 shows a general synthesis scheme for the compounds of the present invention;

in FIG. 2 is a general outline of the synthesis of compounds of the present invention;

in FIG. 3 is a general outline of the synthesis of compounds of the present invention.

The term “alkyl” by itself or as part of another substituent means, unless otherwise indicated, a straight, branched or cyclic hydrocarbon radical or a combination of these hydrocarbon radicals, which (s) can be fully saturated (s), mono

- 3 011439 or polyunsaturated (s), may (gut) include di- and polyvalent radicals and contains the indicated number of carbon atoms (i.e. C1-Ciu means from one to ten carbon atoms). Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, nbutyl, tert-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, their homologues and isomers, for example, n-pentyl , n-hexyl, n-heptyl, n-octyl and the like. An unsaturated alkyl group is a group containing one or more double or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentyl, 2- (butadienyl), 2,4pentadienyl, 3- (1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl and their higher homologues and isomers.

The term "alkylene" by itself or as part of another substituent means, unless otherwise indicated, a divalent radical derived from an alkane, for example, -CH2CH2CH2CH2-, as well as groups defined below by the term "heteroalkylene". Typically, an alkyl (or alkylene) group will contain from 1 to 24 carbon atoms, with groups containing 10 or less carbon atoms being preferred according to the present invention. The term "lower alkyl" or "lower alkylene" means an alkyl or alkylene group with a shorter chain, usually containing eight carbon atoms or less.

The terms “alkoxy”, “alkylamino” and “alkylthio” (or “thioalkoxy”) are used in their usual meaning and refer to alkyl groups attached to the rest of the molecule via an oxygen atom, an amino group or a sulfur atom, respectively. Similarly, the term "dialkylamino" refers to an amino group containing two attached alkyl groups, which may be the same or different.

The term “heteroalkyl” by itself or as part of another substituent means, unless otherwise indicated, a stable straight, branched or cyclic hydrocarbon radical or a combination of these hydrocarbon radicals, including (her) the specified number of carbon atoms and from one or up to three heteroatoms, selected from the group consisting of O, Ν, 81, and 8, where the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternary. Heteroatom (s) O, N and 8 may be located at any position within the heteroalkyl group. The heteroatom 81 may be in any position of the heteroalkyl group, including the position in which the alkyl group is attached to the rest of the molecule. Examples of heteroalkyl include —CH2 — CH2 — O — CH3, —CH _; -CH _; AN-C11 _; . -CH2-CH2 ^ (CH3 -) - CH3, -CH2-8-CH2-CH3, -CH2-CH2, -8 (O) -CH3, -CH2-CH2-8 (O) 2-CH3, -CH = CH-O-CH3, -81 (CH3) s, -CH2-CH = NOCHe and -CH = CH ^ (CH ₃ ) -CH ₃ . Sequentially connected can be no more than two heteroatoms, for example, -ΟΠ ₂ -ΝΠOCH ₃ and -CH ₂ -O-81 (CH ₃ ) s. When a subscript such as (C ₂ -C ₈ ) is used in the definition of a heteroalkyl group, the number of carbon atoms (in this case, 2-8) also includes heteroatoms. For example, it is understood that a “C2 heteroalkyl group” includes in particular —CH2OH (one carbon atom and one heteroatom replacing a carbon atom) and —CH ₂ 8H. The term “heteroalkylene” alone or as part of another substituent means, unless otherwise indicated, a divalent radical derived from heteroalkyl, for example —CH ₂ —CH ₂ —8 — CH ₂ CH ₂ - and —Ο ^^ - Ο ^ Ο ^ -ΝΠCH ₂ -. In heteroalkylene groups, heteroatoms can also occupy one or both terminal positions in the chain (for example, alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). In addition, the determination of alkylene and heteroalkylene linking groups does not imply determining the exact location of the linking group.

The term “cycloalkyl” or “heterocycloalkyl” by itself or as part of another substituent means, unless otherwise indicated, cyclic varieties of “alkyl” or “heteroalkyl”, respectively. In addition, in the heterocycloalkyl, the heteroatom may occupy a position in which the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl and the like. Examples of heterocycloalkyl include 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2 -yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl and the like.

The term “halogen” alone or as part of another substituent means, unless otherwise indicated, a fluorine, chlorine, bromine or iodine atom. In addition, the term “haloalkyl” includes monohaloalkyl and polyhaloalkyl. For example, the term “halogen (C1C4) alkyl” is intended to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term "aryl" by itself or as part of another substituent means, unless otherwise indicated, a polyunsaturated, usually aromatic, hydrocarbon substituent, which may be a single ring or consist of several rings (up to three rings), condensed or connected covalently. The term “heteroaryl” refers to aryl groups (or rings) that contain from zero to four heteroatoms selected from атомов, O, and 8 atoms, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom (s) are optionally quaternary (s) . A heteroaryl group may be attached to the rest of the molecule via a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pi

- 4 011439 rasinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl , 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5indolyl, 1-isoquinolyl, 5-isoquinolyl , 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. Substituents for each of the above aryl or heteroaryl ring systems are selected from the group of acceptable substituents described below.

For brevity, the meaning of the term “aryl” when used in combination with other terms (eg, aryloxy, arylthioxy, arylalkyl), the meaning includes aryl and heteroaryl rings as defined above. Thus, the term “arylalkyl” is intended to include radicals in which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, etc.), including alkyl groups in which a carbon atom (eg, methylene group) substituted, for example, with an oxygen atom (for example, phenoxymethyl, 2-pyridyloxymethyl, 3- (1naphthyloxy) propyl, etc.).

It is intended that each of the terms defined above (for example, “alkyl,” “heteroalkyl,” “aryl,” and “heteroaryl”) include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are presented below.

Substituents for alkyl and heteroalkyl radicals (including groups defined as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) can be various groups selected from -0Β ', = 0, = ΝΒ', = Ν0Β ', -ΝΒ'Β, -δΒ', -halogen, -δίΒ'ΒΒ ', -0С (0) В', -С (0) В ', -С0 ₂ В', -ΟΟΝΒ'Β, -00 (0) ΝΒ'Β, -ΝΒ0 (0) Β ', -ΝΒ'-0 (0) ΝΒΒ''', -ΝΒ € (0) ₂ Β ', -ΝΗ-ϋ (ΝΗ ₂ ) = ΝΗ, - ΝΒ'ϋ (ΝΗ ₂ ) = ΝΗ, -ΝΗ- ^ ΝΗ ₂ ) = ΝΒ ', -δ (0) Β', -δ (0) ₂ Β ', -δ (0) ₂ ΝΒ'Β, -СЫ and -Ν0 ₂ and taken in an amount in the range from zero to (2m + 1), where m is equal to the total number of carbon atoms in such a radical. Β ', Β and Β''' each independently represents H, unsubstituted (C ₁ -C§) alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, alkoxy or thioalkoxy groups or aryl- (C1-C ₄ ) alkyl groups. When Β 'and Β are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 5-, 6- or 7-membered ring. For example, -ΝΒ'Β is meant to include 1-pyrrolidinyl and 4-morpholinyl. It is also understood that from the above discussion of substituents, one skilled in the art can imagine that the term “alkyl” in the broadest sense includes groups such as haloalkyl (for example, —CST ₃ and —CI ₂ CP ₃ ) and acyl (for example, - C (0) SI ₃ , -C (0) ST ₃ , -C (0) CH ₂ OCH ₃ , etc.). Preferably, unless otherwise indicated, the alkyl groups will contain 0-3 substituents, more preferably 0, 1 or 2 substituents.

Similarly, the substituents for aryl and heteroaryl groups are different, selected from halogen, -0Β ', 0C (0J. -ΝΒ'Β, -δΒ', -Β ', -ΟΝ, -Ν0 ₂ , Α0 ₂ Β', -ίΌΝΒ 'Β, - € (0) Β', -OS (Ο) NΒ'Β, ΝΒ'Ό (0) Β ', -ΝΒ € (0) ₂ Β', -ΝΒ'- € (0) ΝΒΒ ', -ΝΗ- ^ ΝΗ ^ ΝΗ, -ΝΒΌ (ΝΗ ₂ ) = ΝΗ, -ΝΗ-ϋ (ΝΗ ₂ ) = ΝΒ ', -δ (0) Β', -δ (0) ₂ Β ', -8 (0 ) ₂ ΝΒ'Β, -Ν ₃ , -CI (PY) ₂ , perfluoro (C ₁ -C ₄ ) alkoxy and perfluoro (C1-C ₄ ) alkyl and are present in an amount ranging from zero to the total number of open valencies on aromatic ring system; wherein Β ', Β and Β''' are independently selected from H, _(C1-C8) alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, ( unsubstituted aryl) - _(C1-C4) alkyl and (unsubstituted aryl) oxy- _(C1-C4) alkyl.

Two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with a substituent of the formula —T — C (O) - (CH ₂ ) _H —I—, where T and independently are —ΝΗ—, —0—, —CH ₂ or single bond, and c. | represents an integer from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with a substituent of the formula —A— (CH ₂ ) _g —B—, where A and B independently represent —CH ₂ -, -0-, -ΝΗ-, -8-, -8 (0) -, -δ (0) ₂ -, -δ (0) ₂ ΝΒ 'or a single bond, and r is an integer from 1 to 3. One of the single bonds of the new rings formed in this way may not necessarily be replaced by a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with a substituent of the formula - (CH ₂ ) ₈ -X- (CH ₂ ) _G where 8 and ΐ independently are integers from 0 to 3, and X represents -0-, -ΝΒ'-, -δ-, -δ (0) -, -δ (0) ₂ - or -δ (0) ₂ ΝΒ'-. Substituent Β 'in -ΝΒ'- and δ (0) ₂ ΝΒ'- selected from hydrogen or unsubstituted _(C1-C6) alkyl.

The term “heteroatom”, as used herein, is intended to mean an atom of oxygen (O), nitrogen (Ν), sulfur (δ), and silicon (δί).

The abbreviation Me, when used in the present description, means methyl (ie —CH ₃ ), the abbreviation "E1". when used in the present description, means ethyl, and the abbreviation "Ry" when used in the description means phenyl.

The term “pharmaceutically acceptable salts” is intended to include salts of compounds that are prepared with relatively non-toxic acids or bases, depending on the particular substituents on the compounds of the present invention. When the compounds of the present invention contain relatively acidic functionalities, base addition salts can be prepared by contacting the neutral form of such compounds with a sufficient amount of the desired base in pure form or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, cal

- 5 011439 tion, ammonium, an organic amine or magnesium salt, etc. When the compounds of the present invention contain relatively basic functionalities, acid addition salts can be prepared by contacting the neutral form of such salts with a sufficient amount of the desired acid in pure form or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, nitric, carbonic, hydrogen carbonate, phosphoric (orthophosphoric), monohydrogen phosphate, dihydrogen phosphate, sulfuric, monohydrogen sulfate, hydrogen iodide or phosphorous and the like. acids, as well as salts derived from relatively non-toxic organic acids, such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberinic, fumaric, almond, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic and .P. acids. They also include salts of amino acids, such as arginate, and the like, and salts of organic acids, such as glucuronic or galactunoric (da1acSiopsi) acids and the like. (see, for example, Vsgds. s1 a1. (1977) 1. Ryatt. 8c1 66: 1-19). Some of the specific compounds of the present invention contain both basic and acidic functionalities, which make it possible to convert these compounds into both basic and acid addition salts.

Neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the starting compound in a convenient manner. The initial form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but with regard to the objectives of the present invention, the rest of the salts are equivalent to the original form of the compounds according to the present invention.

In addition to salt forms, the present invention provides compounds that are prodrug form. Prodrugs of the active compounds described in the present invention are inactive compounds that readily undergo chemical transformations under physiological conditions to produce the active compounds of the present invention. In addition, prodrugs can be converted into active compounds according to the present invention by chemical or biochemical methods ex νίνο. For example, prodrugs can undergo a slow conversion to the active compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

Often, the use of prodrugs is due to the fact that in some cases they can be administered more easily than the active compound. They may, for example, be bioavailable by oral administration, while the active compound is not. A prodrug may also have better solubility in pharmacological compositions than the active compound. A wide range of prodrug derivatives are known in the art, such as prodrugs, the cleavage of which occurs as a result of hydrolysis or oxidation. For example, but without limitation, the prodrug could be a compound of the present invention, which is administered in the form of an ester (“prodrug”), but is then subjected to metabolic hydrolysis to a carboxylic acid, an active ingredient. Additional examples include peptidyl derivatives of the active compound of the present invention.

Some compounds of the present invention may exist in both unsolvated forms and solvated forms, including hydrated forms. Typically, solvated forms are equivalent to unsolvated forms, and are intended to be included within the scope of the present invention. Some compounds of the present invention may exist in a variety of crystalline or amorphous forms. Typically, all physical forms are equivalent for the applications contemplated by the present invention, and are intended to be included within the scope of the present invention.

Some compounds of the present invention contain asymmetric carbon atoms (optical centers) or double bonds; and it is understood that all racemates, enantiomers, diastereomers, geometric isomers and individual isomers are included in the scope of the present invention.

Unless otherwise indicated, the term “stereoisomer” or “stereoomerically pure”, as used herein, means one stereoisomer of a compound that is substantially free of other stereoisomers of the compound. For example, a stereomerically pure compound containing one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound containing two chiral centers will be substantially free of other diastereomers of the compound. Typically, a stereomerically pure compound consists of more than about 80 wt.% One stereoisomer of the compound and less than about 20 wt.% Other stereoisomers of the compound, more preferably, more than about 90 wt.% One stereoisomer of the compound and less than about 10 wt.% other stereoisomers of the compound, even more preferably more than about 95 wt.% one stereoisomer of the compound and less than about 5 wt.% other stereoisomers of the compound, and most preferably, more than about 97 wt.% one stereoisomer inenia and less than about 3 wt.% other stereoisomers of the compound. It should be noted that if the stereochemistry of the structure or part of the structure is not indicated, for example,

- 06 011439 bold or dashed lines, it is understood that the structure or part of the structure includes all its stereoisomers.

Various compounds of the present invention contain one or more chiral centers and can exist as racemic mixtures of enantiomers, mixtures of diastereomers, or as enantiomerically or optically pure compounds. The present invention includes the use of stereomerically pure forms of such compounds, as well as the use of mixtures of these forms. For example, mixtures comprising equal or unequal amounts of enantiomers of a particular compound according to the present invention can be used in the methods and compositions of the present invention. Such isomers can be synthesized by asymmetric synthesis methods or can be separated using standard methods, such as the use of chiral columns or chiral resolving agents (see, for example, 1scis5. 1., c1 a1., Epaibotega, Cassete8e and Is5o1u1up5 (\ uSu1n1sg5s1spss. Wogk, 1981); KhUPst 8.N., s1 a1., Tebayebgop 33: 2725 (1977); E11e1, E.B., Geojesjöts ok ok Satoyoi Sotroipbz (MsSta-NSh, ΝΥ, 1962); ^ 8. N., TaYsz ok Kezoktd Adepb and Orbsa1 KekoShbopk p. 268 (E. E. Eye1, Eb., Looking for. Approx. 1ge Eats Rts88, No. 1ge Oats, ΙΝ, 1972).

The compounds of the present invention may also contain unusual fractions of the atomic isotopes of one or more atoms that make up such compounds. For example, the compound may contain a radioisotope tag, such as, for example, tritium ( ³ N), iodine-125 ( ¹²⁵ Ι) or carbon-14 ( ¹⁴ C).

Radioisotope-labeled compounds are useful as therapeutic agents, for example, anti-cancer therapeutic agents, reagents used in research, for example, as reagents used for binding studies, and as diagnostic tools, for example, radiopharmaceuticals for analysis under conditions of u1uo. It is understood that all isotopic species of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

The term “active,” as used herein, means “effective for modulating,” for example, for inhibiting the function of CXC3.

The term "treatment" ("beab>," 1gsa (1pd "or" bea ^ her "), when used in the present description, refers to a method of alleviating or eliminating the disease and / or its accompanying symptoms. The term" prevention "(" rhcd " , “Rgeuehyshd” or “rtsuee ^^ y *), when used in the present description, refers to a method of protecting a subject from a disease.

The present invention relates to compounds, compositions and methods useful for modulating the activity of a chemokine receptor, in particular CXC3. The compounds of the invention are useful for the treatment of, for example, inflammatory and immunoregulatory disorders and can be administered directly to subjects, for example humans, in the form of pharmaceutical preparations.

The compounds of the present invention are also useful for identifying and / or developing compounds that modulate the function of CXC3.3, for example, CXC3 antagonists, and compounds that are converted into one or more compounds that modulate the CXC33 function under physiological conditions.

The compounds of the present invention are compounds that inhibit at least one function or characteristic of a mammalian CXC3 protein, for example, a human CXC3 protein. The ability of a compound to inhibit such a function can be demonstrated by binding studies (e.g., ligand binding or agonist binding), signal studies (e.g., activation of mammalian C protein, inducing a rapid and transient increase in the concentration of free cytosolic calcium) and / or cell response function (e.g. stimulation of chemotaxis, exocytosis or the release of an inflammatory mediator by leukocytes). Examples of such studies are described in US Patent Application Publications No. 2002/0169159 A1 and 2003/0055054 A1, the contents of which are incorporated herein by reference in their entireties.

The present invention provides compounds that are useful as SCX3 antagonists, useful in particular for the treatment or prophylaxis of inflammatory or immune conditions or disorders.

In accordance with one aspect, the present invention provides a compound of formula (I) (^ -a'H'h-in ³

I where K ^a , K ¹ , K ² , K ³ , K ⁴ , A ¹ , A ⁴ , b, O, X and the subscript n take the values defined below. Compounds of the above formula include, unless otherwise indicated, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

A ¹ and A ⁴ independently represent C (K ^b ) or Ν.

In some embodiments of the present invention, A ⁴ represents Ν.

- 7 011439

In some embodiments of the present invention, A ⁴ is C (E ^b ).

In some embodiments of the present invention, A ¹ represents CH.

In some embodiments of the present invention, A ⁴ is CH.

O is selected from the group comprising a bond, (C ₁ -C ₈ ) alkylene, (C ₂ -C ₈ ) heteroalkylene, -C (O) -, -OC (O) -, -CH ₂ CO-, -CH28O- and -CH28O2-.

In some embodiments of the present invention, O is —C (O) -.

B represents a bond or (C ₁ -C ₅ ) alkylene.

In some embodiments of the present invention, b is a bond, —CH ₂ or —CH ₂ CH ₂ -.

X represents —CH ₂ -, 8O _2, or —C (O) -.

In some embodiments, X is —C (O) -.

K ^{3 is} selected from the group consisting of -OK ', = O, = ΝΒ', = Ν-ΟΚ ', -ΝΒΈ, -8K', -halogen, -8ίΒΈΕ ', -OC (O) 1C-C (O) K ', -CO ₂ K', -CΟXΚ'Κ. -OSSO ^ K, -ΝΒ'Ό ^ Β ', -NΚ'-C (Ο) NΚΒ', -ΝΒ'Ό ^ Β ', -ΝΗ ^ ΝΗ ₂ ) = ΝΗ, -ΝΚΧ (ΝΗ ₂ ) = ΝΗ, -ΝΗ ^ (ΝΗ ₂ ) = ΝΚ ', -8 (O) K', -8 (O) ₂ K ', -8 (O) ₂ XB'K, <Ν and - \ O _; .

K. ¹ 'is selected from the group consisting of -OK', = O, = ΝΚ ', = K-OK', -ΝΚ'Κ, -8K ', -halogen, -8Ж,' ЕК ', -ОС (О) K ', -C (O) K', -CO ₂ K ', -COX ^' K, -OC (O) MK'K, -XBC (O) K ', -MK'-C (O) MKK' , -XBC (O) ₂ K ', -ΝΗC (XH ₂ ) = XN, -ΝΒΧ (ΝΗ ₂ ) = ΝΗ, -ΝΗ- ^ ΝΗ ₂ ) == ΝΚ', -K ', -8 (O) K ', 8 (O) ₂ K', ^ (OUNIK, -CY and -O ₂ .

The subscript η is 0, 1, 2, or 3.

Each K ′, K and K ′ independently represents H, unsubstituted (C ₁ -C ₈ ) alkyl, heteroalkyl, unsubstituted aryl or substituted aryl.

K ¹ is heteroaryl or aryl.

In some embodiments of the present invention, K ¹ is unsubstituted or meta- or para-substituted phenyl, wherein the substituent is halogen, cyano, (C ₂ -C ₈ ) alkyl, (C2-C8) heteroalkyl, (C2-C8) alkoxy, or ( C2-C8) heteroalkoxy.

In some embodiments, implementation of the present invention K ¹ represents paracyanophenyl.

K ^{2 is} selected from the group consisting of hydrogen, halogen, (C ₁ -C ₁₀ ) alkyl, (C ₂ -C ₁₀ ) heteroalkyl, hetero (C ₁ C ₁₀ ) cycloalkyl, (C ₁ -C ₁₀ ) alkylaryl and (C ₂ —C ₁₀ ) heteroalkylaryl or optionally K ² together with b form a 5-, 6-, 7- or 8-membered ring containing from 1 to 3 heteroatoms selected from the group consisting of Ν, O and 8 atoms.

In some embodiments, implementation of the present invention K ² selected from the group including —CH ₃

—CH ₂ OH and

υ

K ^{3 is} absent or selected from the group consisting of H, -SC ⁶ K ⁷ , -8 (O) tK ⁵ , ^ (О ^ МЩ ^ K ⁹ , 8 (Ο) tN (Κ ⁸ ) СΗ2Κ ⁶ , -Н (К ⁸ ) 8O2K ⁵ , AIPSN-K,

or, optionally, K ³ together with K ² can form a 4-, 5-, 6-, 7- or 8-membered ring containing from 1 to 3 heteroatoms selected from the group consisting of Ν, O and 8 atoms.

In some embodiments of the present invention, K ^{3 is} selected from the group consisting of -H, -8O2CH3, -8O2CH2CH3, ⁰ / = \ nnO -O - <3 ^s >>

CH (CH3) CH3,

Me

In some embodiments, implementation of the present invention-b-K ³ together represent

- 8 011439

K ⁴ is selected from the group consisting of (C1-C ₂ o) alkyl, (C ₂ -C ₂₀₎ heteroalkyl, heteroaryl, aryl, heteroaryl _(C1-C6) alkyl, heteroaryl _(C2-C6) heteroalkyl, aryl ( C ₁ -C ₆ ) alkyl and aryl (C ₂ -C ₆ ) heteroalkyl.

In some embodiments, implementation of -C-K ¹ represents

(Ii):

K ^{5 is} selected from the group consisting of (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) heteroalkyl, aryl and heteroaryl.

K ⁶ and K ⁷ independently represent hydrogen, (C ₁ -C ₈ ) alkyl or (C ₂ -C ₈ ) heteroalkyl.

K ⁸ represents hydrogen, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) heteroalkyl, heteroaryl or aryl.

K ⁹ is (C ₁ -C ₈ ) alkyl.

K ¹⁰ is aryl.

Ζ represents CH or N.

X ¹ represents a bond, (C ₁ -C ₈ ) alkylene or (C ₁ -C ₆ ) heteroalkylene.

Υ ¹ represents (C ₁ -C ₆ ) alkylene.

The subscript m is 0, 1, or 2.

In some embodiments, the compound is represented by the formula

And where K ^a , K ² , K ³ , K ⁴ , A ¹ , A ⁴ , b, O. X and the subscript η take the values described above for formula I, K ¹¹ represents hydrogen, (C ₁ -C ₈ ) alkyl or (C ₂ -C ₈ ) heteroalkyl.

In some embodiments of the present invention, K ¹¹ is —H, —CH ₃ , CH ₂ CH _3, or —CH ₂ CE ₃ .

In some embodiments, implementation of the present invention K ² represents methyl and -K ³ represents

In some embodiments, implementation of the present invention K ³ selected from the group including

-8O2CH3, -8O2CH2CH3

F> O ΥΌ>

Me

In some embodiments, the compound of the present invention corresponds to formula (III)

K ³

III where K ^a , K ¹ , K ³ , K ⁴ , A ¹ , A ⁴ , Υ, O, X and the subscript n take the values defined below.

Compounds of the above formula include, unless otherwise indicated, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

A ¹ and A ⁴ independently represent C (K ^b ) or N.

In some embodiments, implementation of the present invention And ⁴ represents N.

In some embodiments, implementation of the present invention And ¹ represents C (K ^b ).

- 9 011439

In some embodiments, implementation of the present invention And ⁴ represents C (K ^b ).

In some embodiments, implementation of the present invention And ⁴ represents-CH ₂ -.

O is selected from the group consisting of bond, _(C1-C8) alkylene, _(C2-C8) heteroalkylene, -C (O) -, -OC (O) -, -CH2CO-, and -SN28O- -SN28O2- .

In some embodiments of the present invention, O is —C (O) -.

V and Υ each independently represents a carbon atom or a heteroatom, and V and Υ joined together form a 5- or 6-membered cycloalkyl or cycloheteroalkyl ring, where the 5- or 6-membered ring is unsubstituted or substituted with halogen, ΝΗ ₂ , ΝΟ ₂ , ( C ₁ -C ₂ o) alkyl, (C ₂ -C ₂₀ ) heteroalkyl, heteroaryl, aryl, heteroaryl (C ₁ -C ₆ ) alkyl, heteroaryl (C ₂ -C ₆ ) heteroalkyl, aryl (C2-C6) alkyl, and aryl (C2-C6) heteroalkyl.

X represents —CH ₂ -, 8O _2, or —C (O) -.

In some embodiments of the present invention, X is —C (O) -.

K ^{3 is} selected from the group consisting of -OK ', = O, = ΝΚ', = Ν-ΟΚ ', -ΝΚ'Κ, -8K', -halogen, -8ίΚ'ΚΚ ', -OC (O) K', -C (O) K ', -CO ₂ K', -SOKHK. -OS (O) YAK'K, -YAKS (O) K ', -MK'-S (O) IKK', -YAKS (O) ₂ K ', -ΝΗ ^ ΝΗ ₂ ) = ΝΗ, -ЫК'С (ΝΗ ₂ ) = ΝΗ, -ΝΗ-ϋ (ΝΗ ₂ ) = ΝΚ ', -8 (О) К', -8 (О) ₂ К ', -8 (О) ₂ ЯК'К, -ΟΝ and - \ Oh _; .

K ^L is selected from the group consisting -tuples ', = O, = ΝΚ', = ΝΌΚ ' , -ΝΚ'Κ, -8K', -halogen, -81K'KK ', OC (O) R', -C ( O) K ', -CO ₂ K', -SOKHK. -OS (O) YAK'K, -YAKS (O) K ', -MK'-S (O) MKK', -YKS (O) ₂ K ', -ΝΗС (МН ₂ ) = МН, -ХГК'С (ΝΗ ₂ ) = ΝΗ, -MN-S (MN ₂ ) = No. ', -K', -8 (O) K ', -8 (O) ₂ K', -8 (O) ₂ YAK'K, -ΌΝ and - \ O _; .

The subscript η is 0, 1, 2, or 3.

K ', K and K' each independently represents H, unsubstituted (C ₁ -C ₈ ) alkyl, heteroalkyl, unsubstituted aryl or substituted aryl.

K ¹ is heteroaryl or aryl.

In some embodiments of the present invention, K ¹ is unsubstituted or meta- or para-substituted phenyl, wherein the substituent is halogen, cyano, (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) heteroalkyl, (C ₁ - C ₈ ) alkoxy or (C ₁ -C ₈ ) heteroalkoxy.

In some embodiments, implementation of the present invention K ¹ represents

In some embodiments of the present invention, K ¹ is para-cyanophenyl.

K ^{3 is} absent or selected from the group consisting of —H, —SNA ⁶ K ⁷ , -8 (O) tK ⁵ , -8 (O) ^ (K ⁸ ) K ⁹ , 8 (O) tMK ⁸ ) CH2K ⁶ , - \ (K ⁸ ) 8O; K '. - \ (K ⁸ ) CH; K '.

K ^{4 is} selected from the group consisting of (C ₁ -C ₂₀ ) alkyl, (C ₂ -C ₂₀ ) heteroalkyl, heteroaryl, aryl, heteroaryl (C ₁ -C ₆ ) alkyl, heteroaryl (C ₂ -C ₆ ) heteroalkyl, aryl (C ₁ -C ₆ ) alkyl and aryl (C ₂ -C ₆ ) heteroalkyl.

In some embodiments, implementation of the present invention -O-K ¹ represents

K ^{5 is} selected from the group consisting of (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) heteroalkyl, aryl and heteroaryl.

K ⁶ and K ⁷ independently represent hydrogen, (C ₁ -C ₈ ) alkyl or (C ₂ -C ₈ ) heteroalkyl.

K ⁸ represents hydrogen, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) heteroalkyl, heteroaryl or aryl.

K ⁹ is (C ₁ -C ₈ ) alkyl.

K ¹⁰ is aryl.

In some embodiments of the present invention, the compound corresponds to formula (IV) · ^Α γ ^χ '''* ¹ „ „V / ³

K ³

IV where K ^a , K ¹ , K ³ , K ⁴ , A ¹ , Α ⁴ , Υ, O. X and the subscript η take the values defined above in formula III, and V ¹ , V ² and V ³ take values, defined below.

V ^{1 is} absent or selected from the group consisting of -0-, -8-, -8 (0) -, -8 (Θ) ₂ -, -C (O) -, -CH ₂ - or ΝΚ ¹¹ -.

In some embodiments, implementation of the present invention V ¹ represents-CH ₂ -.

V ² and Υ independently represent —CH ₂ -, —CHK ¹² -, —CH =, —SK ¹² =, —ΝΗ-, —Ν = or —ΝΚ ¹² -.

In some embodiments, implementation of the present invention V ² represents -Ν =, -ΝΗ or -Y (CH3) -.

V ^{3 is} absent or represents -0-, -8-, -8 (0) -, -8 (0) ₂ -, -CH ₂ -, -СНК ¹³ -, -СН =, -СК ¹³ =, -ΝΗ -, -Ν = or -ΝΚ ¹³ -.

In some embodiments, implementation of the present invention, V ¹ , V ³ and Υ each represents-CH 2 -.

In some embodiments, implementation of the present invention, V ¹ is —CH ₂ -, V ² is —Ν =, V ^{3 is} absent, and Υ is —CH = or —CK ¹² -.

In some embodiments, implementation of the present invention, V ² represents —Y (CH ₃ ) or —ΝΗ—.

A ¹ and A ⁴ independently represent C (K ^b ) or Ν.

K ^{11 is} selected from the group consisting of hydrogen, (C ₁ -C ₈ ) alkyl, (C ₁ -C ₈ ) heteroalkyl, aryl, and heteroaryl.

K ¹² and K ¹³ independently represent (C ₁ -C ₂₀ ) alkyl, (C ₂ -C ₂₀ ) heteroalkyl, heteroaryl, aryl, heteroaryl (C ₁ -C ₆ ) alkyl, heteroaryl (C ₂ -C ₆ ) heteroalkyl, aryl (C ₁ -C ₆ ) alkyl; and aryl (C ₂ -C ₆ ) heteroalkyl.

In some embodiments, implementation of the present invention K ¹ represents paracyanophenyl.

In some embodiments, the compound of Formula (V)

ν where K ^a , K ^b , K ¹ , K ³ , K ⁴ , Υ, O. V ² , V ³ and subscript η take the values defined above.

It is easy to imagine that the compounds of the present invention exist as stereoisomers. In some embodiments, the compound of formula (I) is a racemic compound. In some embodiments, the compound of formula (I) comprises a mixture of (8) and (K) enantiomers.

In some embodiments, implementation of the present invention, the compound corresponds to the formula (1A) (Pa):

above for formula I.

In other embodiments, implementation of the present invention, the compound corresponds to the formula (1b)

above for formula I.

In further embodiments, the present invention provides a racemic mixture of compounds! A and! B.

In some embodiments, the compound is represented by the formula

- 11 011439 (P)

above for formula II.

In other embodiments of the present invention, the compound corresponds to the formula

_To 4-a 'h-to ³

above for formula II.

In further embodiments, the present invention provides a racemic mixture of compounds Na and II.

In some embodiments, the compound of the present invention is a solid. For example, in some embodiments, the compound of the present invention is in crystalline form. In some embodiments, the compound is amorphous.

In some embodiments, the compound of the present invention in crystalline form has a purity of at least 80%, at least 90%, at least 92%, at least 95%, at least 97%, or at least 98%.

Compounds according to the present invention can be obtained by various synthetic or semi-synthetic methods. In FIG. 1-3 and below in the examples presents various ways of synthesizing the compounds according to the present invention. The synthesis of suitable starting materials may be carried out in accordance with methods known or obvious to a person skilled in the art, or the starting materials may be commercially available. For example, such substances can be obtained in accordance with the methods described in applications for US Patent No. 2002/0160159 A1 and 2003/0055054 A1 and in International Publication No. \ ¥ O 02/83143, the contents of which are incorporated into this description in its entirety .

For example, the compounds of the present invention can be prepared in accordance with the following scheme or its variants that are obvious to a person skilled in the art:

but

ΝΗ ₂

B

from

In the above diagram, product c can be obtained from the starting material a, obtained, for example, in accordance with the publication procedure \ UO 02/83143 using methods and reagents obvious to a person skilled in the art. For example, to obtain an intermediate product b, the starting material a can be reacted with an activated derivative (-C-K ³ ). In turn, in order to obtain a product with an intermediate product, b can be reacted with an activated derivative (OK ¹ ). Numerous examples of the syntheses of the compounds of the present invention are presented in the examples below, including starting materials, reagents, reaction conditions, intermediates and final products. Additional methods for preparing the compounds of the invention will be apparent from the foregoing scheme, embodiments of the schemes described in the examples below, and descriptions provided.

One skilled in the art will understand that substituents can be added or changed before, during, or after the preparation of heterocyclic scaffolds, and one skilled in the art will be able to appropriately select conditions (e.g., temperatures, solvents, etc.). In addition, one of ordinary skill in the art will appreciate that protecting groups may be necessary to produce certain compounds, and will represent conditions compatible with the selected protecting group.

Typical methods and examples described in the invention are illustrative examples.

- 12 011439 of the present invention and should not be construed as limiting its scope.

In accordance with another aspect, the present invention provides pharmaceutical compositions for modulating chemokine receptor activity in humans and animals. Compositions include a compound of the present invention with a pharmaceutically acceptable carrier or diluent.

The term "modulation" or "modulation of the activity of chemokine receptors", when used in various forms in the description, is intended to include antagonism, agonism, partial antagonism and / or partial activity agonism associated with a particular chemokine receptor, preferably the CXCB3 receptor. The term “composition”, as used herein, is intended to include a product containing the listed ingredients (and in specific amounts, if indicated), as well as any product that is directly or indirectly the result of a combination of specific ingredients in specific quantities. The term “pharmaceutically acceptable” means a carrier, diluent or excipient that must be compatible with the other ingredients of the preparation and not adversely affect the recipient.

Pharmaceutical compositions for administration of the compounds of the present invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacopeia. All methods include the step of combining the active ingredient with a carrier that comprises one or more accessory ingredients. Typically, pharmaceutical compositions are prepared by thoroughly uniformly mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both of these carriers, and then, if necessary, molding the article into the desired preparation. The compound is administered in a pharmaceutical composition in an amount sufficient to produce the desired effect on the course or condition of the disease.

Pharmaceutical compositions containing the active ingredient may be presented in a form suitable for oral administration, for example, in the form of tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral administration can be obtained in accordance with any method known in the field of pharmaceutical compositions, and such compositions may contain one or more adjuvants selected from the group including, sweeteners, flavoring agents, coloring agents and preservatives, to provide pharmaceutically refined and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. Such excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating additives and disintegrants, for example, corn starch or alginic acid; binding agents, for example starch, gelatin or acassia, and glidants, for example, magnesium stearate, stearic acid or talc. The tablets may not be coated or coated by known methods to slow the disintegration and absorption in the gastrointestinal tract and thus provide a prologged effect over a longer period of time. For example, a longer decomposition material such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated by the methods described in US Patent Nos. 4,256,108; 4166452 and 4265874, to obtain osmotic therapeutic tablets for the controlled release of the active substance.

Oral preparations can also be presented in the form of hard gelatin capsules in which the active ingredient is mixed with a solid inert diluent, for example calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules, where the active ingredient is mixed with water or an oil medium, for example peanut butter, liquid paraffin, or olive oil.

Aqueous suspensions contain the active ingredients in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspensions such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth resin and gumarabic; dispersing or wetting agents may be a natural phosphatide, for example lecithin, condensation products of alkylene oxide with fatty acids, for example polyoxyethylene stearate, condensation products of ethylene oxide and long carbon chains, for example heptadecaethenoxycetanol, condensation products of ethylene oxide with partial fatty acids , polyoxyethylene sorbitol monooleate, or partial ester condensation products of ethylene oxide, obtaining fatty acids and hexitic anhydrides, for example polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

- 13 011439

Oily suspensions may be prepared by suspending the active ingredient in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners, such as those mentioned above, and flavoring agents may be added to provide a palatable oral preparation. Such compositions may be protected by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparing an aqueous suspension by adding water include the active ingredient in admixture with a dispersant or wetting agent, a suspension and one or more preservatives. Suitable examples of dispersants or wetting agents and suspensions are mentioned above. Additional excipients, for example, sweeteners, flavoring agents and coloring agents, may also be present.

The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or peanut oil, or mineral oil, for example liquid paraffin, or mixtures thereof. Suitable emulsifiers can be natural resins, for example gum arabic or tragacanth, natural phosphatides, for example soybeans, lecithin, or esters or partial ester derivatives of fatty acids and hexitic anhydrides, for example sorbitan monooleate, as well as condensation products of said partial partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavorings.

Syrups and elixirs can be prepared with sweeteners, for example glycerol, propylene glycol, sorbitol, or sucrose. Such preparations may also contain an emulsifier, preservative and flavoring and coloring agents.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. Such a suspension can be obtained in accordance with methods well known in the art using suitable dispersants or wetting agents and suspensions as listed above. The sterile injectable preparation may also be a solution or suspension for injection in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Suitable carriers and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, any sterile, fixed oil may be used as a solvent or suspending medium for this purpose. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid have been used to prepare injectable preparations.

The compounds of the present invention can also be used in the form of suppositories for rectal administration of a drug. Such compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at room temperature but liquid at the temperature of the rectum and therefore will melt in the rectum to release the drug. Such substances include, but are not limited to, cocoa butter and polyethylene glycols.

For topical use, creams, ointments, gels, solutions or suspensions, and the like, containing the compounds of the present invention are used. The term "topical application", when used in the present description, means the use of washing solutions and rinses for the oral cavity.

The pharmaceutical composition and method according to the present invention may further include other therapeutically effective compounds, which are described in the description and which are usually used to treat or prevent the above pathological conditions.

In accordance with another aspect, the present invention provides methods for treating CXC3-mediated conditions or diseases by administering to a subject suffering from such a disease or condition a therapeutically effective amount of a compound or composition according to the present invention.

The term “subject,” as used herein, includes animals, such as mammals, including, but not limited to, primates (eg, humans), cattle, sheep, goats, horses, pigs, dogs, cats, rabbits, rats, mice etc.

The phrase “SCHSC-mediated condition or disease” and the phrases and terms derived from it refer to a condition characterized by an unusual, for example, less or greater than normal SCXC3 activity. Unusual CXSC3 activity may result from the expression of CXC3 in cells that do not usually express CXC3, increased CXC3 expression (leading, for example, to inflammatory and immunoregulatory disorders and diseases), or reduced CXC3 expression (leading, for example, to some types of cancer and angiogenic disorders and disorders associated with the development of blood vessels). Unusual functional

- 14 011439 activity of CXCK3 can occur as a result of the expression of CXC3 in cells that usually do not express CXC3, increased CXC3 expression (leading, for example, to inflammatory and immunoregulatory disorders and diseases) or reduced CXC3 expression. The unusual functional activity of CXC3 can also arise as a result of the secretion of chemokine by cells that do not usually secrete CXC chemokine, increased expression of chemokine (leading, for example, to inflammatory and immunoregulatory disorders and diseases) or decreased expression of chemokine. SCX3-mediated condition or disease can be wholly or partially carried out by the unusual functional activity of SCX3. However, the CXC3-mediated condition or disease is a disease in which modulation of CXC3 leads to some effect on the condition or disease in question (for example, the CXC3 antagonist leads to some improvement in health, at least in some patients).

The term “therapeutically effective amount” means the amount of a compound in question that elicits a biological or medical response from a tissue, system, animal or person sought by a researcher, veterinarian, doctor or other physician or which is sufficient to prevent the development or alleviation to some extent of one or more symptoms diseases to be treated.

Diseases or conditions associated with inflammation, infection or cancer can be treated with the compounds and compositions of the present invention. In one group of embodiments of the invention, diseases or conditions, including chronic diseases, of humans or other species can be treated with inhibitors of CXC3 function. These diseases or conditions include (1) inflammatory or allergic diseases, such as systemic anaphylactic or hypertensive responses, allergic reactions to drugs, allergic reactions to insect bites, and food allergies; inflammatory bowel diseases such as Crohn’s disease, ulcerative colitis, ileitis and enteritis; vaginitis; psoriasis and inflammatory dermatoses, such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis; spordyloarthropathy; scleroderma; asthma and respiratory allergic diseases such as allergic rhinitis, allergic lung diseases, etc., (2) autoimmune diseases such as arthritis (rheumatoid and psoriatic), multiple sclerosis, systemic lupus erythematosus, type I diabetes, glomerulonephritis and t .p., (3) graft rejection (including allograft rejection and the graft versus host reaction) and conditions associated with it, (4) other diseases in which undesirable inflammatory responses need to be inhibited, for example, ather sclerosis, myositis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, conjunctivitis, otitis media, chronic obstructive pulmonary disease, sinusitis and Behcet's syndrome. In another group of embodiments of the present invention, diseases or conditions are treated with agonists of CXC3 function. Examples of diseases to be treated with agonists of SCX3 function include cancers, diseases in which angiogenesis or neovascularization plays an important role (neoplastic diseases, retinopathy and macular degeneration), infectious diseases and immunosuppressive diseases.

Preferably, the presented methods relate to the treatment or prevention of diseases or conditions selected from neurodegenerative diseases (e.g., Alzheimer's disease), multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, atherosclerosis, encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, psoriasis, eczema, urticaria, type I diabetes, asthma, conjunctivitis, otitis media, allergic rhinitis, chronic obstructive pulmonary disease, sinusitis, dermatitis, inflammatory disease of the thick bowel, ulcerative colitis, Crohn’s disease, Behcet’s syndrome, gout, cancer, viral infections (e.g. HIV), bacterial infections, and conditions related to organ transplantation or skin transplantation. The term “conditions associated with organ transplantation” is intended to include conditions associated with bone marrow transplantation and whole organ transplantation (eg, kidney, liver, lung, heart, pancreas, or combinations thereof).

Diseases or conditions that can be treated with the compounds and compositions of the present invention are typically associated with (1) inflammatory or allergic diseases, (2) autoimmune diseases, (3) transplant rejection, and (4) other diseases in which undesirable inflammatory responses should be inhibited as described above. For example, restenosis after surgery such as vascular plastic surgery is usually associated with atherosclerosis and can be treated with the compounds and compositions of the present invention.

Depending on the disease to be treated and the condition of the subject, the compounds according to the present invention can be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, Ju, intracisternally or infused, subcutaneous injection or implantation), spray inhalation, nasal, vaginal, rectal , sublingual or topical routes of administration, and preparations based on the compounds of the present invention may contain a single active compound or mixture of active compounds and are suitable unit dosage formulations containing conventional netok

- 15 011439 pharmaceutically acceptable carriers, adjuvants and diluents suitable for each route of administration.

In the treatment or prevention of conditions that require modulation of the chemokine receptor, a suitable dosage will usually be in the range of about 0.001 to 100 mg per kg of patient’s body weight per day and may be administered in a single dose or in multiple doses. Preferably, the dosage level will be from about 0.01 to about 25 mg / kg per day; more preferably, from about 0.05 to about 10 mg / kg per day. A suitable dosage level may be from about 0.01 to 25 mg / kg per day, from about 0.05 to 10 mg / kg per day, or from about 0.1 to 5 mg / kg per day. Within this range, the dosage may be from 0.005 to 0.05, from 0.05 to 0.5, or from 0.5 to 5.0 mg / kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing from 1.0 to 1000 mg of active ingredient, preferably 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000, 0 mg of active ingredient for symptomatic dosage adjustment that is administered to the patient to be treated. Compounds can be administered on a regimen of 1 to 4 times a day, preferably once or twice a day.

However, it is obvious that the specific dosage level and frequency of dosing for any particular patient may vary and will depend on various factors, including the activity of the particular compound used, metabolic stability and duration of action of the compound, age, body weight, general health, gender, diet nutrition, method and time of administration, rate of excretion from the body, a combination of drugs, the severity of a particular condition and the host organism to be therapeutically to whom to treat.

The compounds of the present invention can be combined with other compounds useful for the treatment or prophylaxis of inflammatory and immune disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, and the pathologies listed above. In many examples, compositions that include a compound of the present invention and an alternative or second therapeutic drug, when administered, have additional or synergistic effects.

For example, in the treatment or prevention of inflammation, the compounds of the present invention can be used in combination or in combination with an anti-inflammatory agent or analgesic, such as an opiate agonist, a lipoxygenase inhibitor, for example, a 5 lipoxygenase inhibitor, a cyclooxygenase inhibitor, for example, a cyclooxygenase-2 inhibitor, an interleukin inhibitor, e.g. interleukin-1 inhibitor, ΝΜΌΑ antagonist, nitric oxide inhibitor or nitric oxide synthesis inhibitor, non-steroidal anti-inflammatory avg. dstvom or a cytokine-suppressing antiinflammatory agent, for example with a compound such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindak, tenidap, and the like Similarly, the subject compounds may be administered with a pain relieving compound; a potentiator such as caffeine, H2 antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudo-ephedrine, oxymetazoline, efinephrine, naphazoline, xylometazoline, propylhexedrine or levodeoxyoxyhedrine; an antitussive, such as codeine, hydrocodone, karamifen, carbetapentane or dextromethorphan; diuretic; and a sedative or non-sedative antihistamine. Similarly, the compounds of the present invention can be used in combination with other drugs that are used to treat / prevent / suppress or alleviate diseases or conditions for the treatment of which the compounds of the present invention are useful. Such additional drugs may be administered by the method and in an amount usually used in its application, simultaneously or sequentially with the compound of the present invention. When a compound of the present invention is used simultaneously with one or more additional drugs, a pharmaceutical composition including, in addition to the compounds of the present invention, such additional drugs is preferred. Accordingly, the pharmaceutical compositions of the present invention include pharmaceutical compositions that also contain one or more additional active ingredients in addition to the compound of the present invention. Examples of additional active ingredients that can be combined with a compound of the present invention and administered separately or in the same pharmaceutical compositions include, but are not limited to, (a) νΤΑ-4 antagonists, (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone and hydrocortisone; (c) immunosuppressants, such as cyclosporine (cyclosporin A, 8apy1ttipe®, Νοοη-ιΙ®), tacrolim (PK-506, RogodgaT®), rapamycin (sirolim, Karatipe®) and other immunosuppressants related to type PK-506 immunosuppressants, and mycophenolate, for example mycophenolate-mofetil (Ce11Cer1®); (i) antihistamines (H1-histamine antagonists) such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenylhydramine, diphenylpyraline,

- 16 011439 tripelennamine, hydroxyzine, methyldazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazolin, pheniramine-pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, decarbetoxyloratadine; (e) non-steroidal anti-asthma drugs, such as a f2-agonist (terbutaline, metaproterenol, phenoterol, isoetarin, albuterol, bitolterol and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leuklastlucrst, ZKV-106203), leukotriene biosynthesis inhibitors (zileuton, ΒАΥ-1005); (Ί) nonsteroidal antiinflammatory drugs (pop 81ego1ba1 ACP 1pLatta OSU adeyk - kZAYu) such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen , naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, thiaprofenic acid and thioxaprofen), derivatives of acetic acid (indomethacin, acemetacin, aclofenac, clidanac, diclofenac, fenclofenac, phenclosinic acid, fentiazac, irofu zoxepack, ospinac, sulindac, thiopinac, tolmetin, zidomethacin and zomepirac); derivatives of fenamic acid (flufenamic acid, meclofenamic acid, mefenamic acid, nifluminic acid and tolfenamic acid), derivatives of biphenylcarboxylic acid (diflunisal and flufenizal), oxycams (isoxicam, pyroxicam, sudoxicamic acid and tenoxylisalacyl isocyanic acid) apazone, piperilone-free, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); (e) cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib (Ce1eBex®) and rofecoxib (νίοχχ®); Type IV phosphodiesterase inhibitors (ΡΌΕ-Γν); (ί) gold compounds such as auranofin and aurothioglucose; (]) Type IV phosphodiesterase inhibitors (REE-III); (k) other chemokine receptor antagonists, in particular CCK1, CCK2, CCK3, CCK5, CCK6, CCK8 and CCK10 / (1) cholesterol-lowering agents such as HMO-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atator and other statins), sequesters (cholestyramine and colestipol), nicotinic acid, derivatives of fenofibric acid (gemfibrozil, clofibrate, fenofibrate and benzofibrate) and probucol; (t) antidiabetic agents such as insulin, sulfonylureas, biguamides (metformin), α-glucosidase inhibitors (acarbose) and glitazone (troglitazone and pioglitazone); (o) beta-interferon preparations (interferon (β-1α, interferon (β-1β; (o) etanercept (EpBe1®)), (p) therapeutic antibodies such as orthoclone (OCTZ), daclizumab ^ eparax), infliximab ( Ketyabe®), basiliximab (81ti1ec1®) and antibodies to anti-CO40 ligands (for example, MKP-1); and (p. |) Other compounds such as 5-aminosalicylic acid and its prodrugs, hydroxychloroquine, Ό-penicillamine, antimetabolites, such as azathioprene and 6-mercaptopurine, and chemotherapeutic agents that are cytotoxic to cancer cells. According to the present invention, the second active ingredient may vary and will depend on the effective dose of each ingredient. Usually, an effective dose of each active ingredient will be used. Thus, for example, when a compound of the present invention is combined with a csAGO, the weight ratio of the compound of the present invention and csAGO is usually will be in the range from about 1000: 1 to about 1: 1000, preferably from about 200: 1 to about 1: 200. Combinations of a compound of the present invention and additional active ingredients will usually also be in the above range of values, but in each case an effective dose of each active ingredient should be used.

Immunosuppressants included in the scope of the present invention further include, but are not limited to, leflunomide, KAI001, EVE080, ΕΤΥ720, CTLA-4, therapeutic antibodies such as orthoclone (OCTZ), daclizumab Separah) and basiliximab (Z1ti1es1®), and antimycocytes globulins such as thymoglobulins.

In particularly preferred embodiments of the invention, the presented methods are directed to the treatment or prophylaxis of multiple sclerosis using the compound of the present invention alone or in combination with a second therapeutic agent selected from betaserone, avonex, azathioprene ^ tiget®, [tigap®), capoxon, prednisone and cyclophosphamide. With combined use, the attending physician may prescribe a combination of therapeutic agents or the administration may be consistent.

In further particularly preferred embodiments of the invention, the methods provided herein relate to the treatment or prophylaxis of rheumatoid arthritis, wherein the compound of the present invention is administered alone or in combination with a second therapeutic agent selected from the group consisting of methotrexate, sulfasalazine, hydroxychloroquine, cyclosporin A, I- penicillamine, infliximab (Ketuabe®), etanercept (EpBe1®), auranofin and aurothioglucose.

In yet another particularly preferred embodiment, the methods provided herein relate to the treatment or prophylaxis of the condition of organic transplants, wherein the compound of the invention is used alone or in combination with a second therapeutic agent selected from the group consisting of cyclosporin A, EC-506, rapamycin, mycophenolate , prednisolone, azathioprene, cyclophosphamide and antilymphocyte globulin.

- 17 011439

Examples

The reagents and solvents used in the examples below can be obtained from commercial sources, such as Λΐάποίι Syetka1 Co. (MPtaikee, ^ ίκ., IL8L). ¹ H NMR spectra were recorded on a Vgikeg 500 ΜΗΖ ΝΜ ^ spectrometer. The peaks of importance are listed in the table in the following order: number of protons, multiplicity (s - singlet; d - doublet; t - triplet; sq. - quartet; m multiplet; broad.s - broadened singlet) and the associated constant (s) in Hertz (Hz). Mass spectrometric analysis by electrospray ionization method (E8C is carried out on an NESHCHEP-Raskagb 1100 Μ 8 электро electrospray mass spectrometer using HP1 100 HPLC (HPLC) for sample delivery. Mass spectrometric results are recorded as mass to charge ratio. Each compound is dissolved in methanol to give a concentration of 0 , 1 mg / ml and 1 μl of the solution are injected with a delivery solvent into a mass spectrometer, which scans from 100 to 1500 Da. Each compound can be analyzed in the positive mode E8I using by using an acetonitrile / water (1: 1) mixture with 1% acetic acid as the delivery solvent. Each compound can be negatively analyzed using a 2 mM solution of ΝΗ / OLs in acetonitrile / water as the delivery solvent.

Example 1

Scheme A

ΝΗϊ

Me

G1a (0Ac), VN

DCE; -46'C

Eoeg ⁰

EPC, NOVT, CMM DMF, K.T.

Α1 D2 1

Compound 1 is synthesized from A1 in two stages, as shown in Scheme A.

Compound A1 is synthesized in accordance with the procedure described in International Publication No. \ ¥ O 02/83143 (Scheme 3, p. 77), which is fully incorporated into the description by reference.

(K) -3- (4-Ethoxyphenyl) -2- {1 - [(1-isopropylpiperidin-4-ylmethyl) amino] ethyl} -3H-quinazolin-4-one (A2).

To a solution of 18.7 g of 1-isopropylpiperidine-4-carbaldehyde (0.12 mol, 1.00 eq.), Dissolved in 300 ml of 1,2-dichloroethane, cooled to -45 ° C, in three equal portions with an interval of 5 37.3 g of A1 (0.12 mol, 1.00 equiv.) are added per minute. The mixture was stirred at -45 ° C for 15 minutes, after which 39 g of sodium triacetoxyborohydride (0.18 mol, 1.50 equiv.) Were added in three equal portions. The reaction mixture was allowed to slowly warm from −45 ° C. to room temperature overnight. A saturated aqueous solution of sodium bicarbonate is added to the mixture until a pH of 9-10 is reached in the aqueous layer. The separated aqueous layer was extracted twice with dichloromethane. The combined organic layers are dried over magnesium sulfate, filtered and concentrated in vacuo to give A2 as a solid glassy substance, which is used further without further purification.

Ή NMR (400 MHz; C!) CJ; T = 298.1 K) δ 1.01 (d, 1 = 6.6 Hz, 6H), 1.11-1.29 (m, 2H), 1.23 (d, 1 = 6.6 Hz, 3H), 1.11-1.41 (m, 1H), 1.46 (t, 1 = 6.9 Hz, 3H), 1.72 (dd, 1 = 14.2, 33.2 Hz, 2H ), 1, 98-2.20 (m, 3H), 2.20-2, 37 (m, 2H), 2.58-2.73 (m, 1H), 2.78-2.92 (m , 2H), 3.43 (dd, 1 = 7.6, 7.6 Hz, 1H), 4.10 (qt, 1 = 6.9 Hz, 2H), 6.97-7, 08 ( m, 2H), 7.08-7.18 (m, 2H), 7.46 (dd, 1 = 8.5, 8.5 Hz, 1H), 7.69 (d, 1 = 8.5 Hz , 1H), 8.27 (d, 1 = 8.5 Hz, 1H) ppm.

(K) -№ {1- [3- (4-Ethoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -2- (4-fluoro-3-trifluoromethylphenyl) -№ (1- isopropylpiperidin-4-ylmethyl) acetamide (1).

To a mixture of 49.3 g of A2 (0.11 mol, 1.00 equiv.) And 29.3 g of 4-fluoro-3- (trifluoromethyl) phenylacetic acid (0.13 mol, 1.20 equiv.) In 120 ml Ν, Ν-dimethylformamide (DMF) and 40 ml of dichloromethane at room temperature add 12 ml of Ν-methylmorpholine (ΝΜΜ) (0.11 mol, 1.00 equiv.) And 14.9 g of 1-hydroxybenzotriazole (HOBT) (0.11 mol , 1.00 equiv.). To the solution, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EES) (0.22 mol, 2.00 equiv.) Was added in two equal portions at intervals of 5 minutes. The reaction mixture was stirred at room temperature for 16 hours, then transferred to 800 ml of ethyl acetate and washed six times successively with saturated aqueous sodium hydrogen carbonate and saturated aqueous salt solution. The organic extract was dried over magnesium sulfate, filtered and concentrated in vacuo to give a solid glassy product. The product was purified by recrystallization from diethyl ether to give 41 g 1 as a colorless solid.

Ή NMR (400 MHz; δ ..- DMSO; T = 393 K): δ 0.92 (d, 1 = 6.6 Hz, 6H), 0.95-1.20 (m, 2H), 1, 35 (t, 1 = 7.0 Hz, 3H), 1, 32-1.50 (m, 2H), 1.50 (d, 1 = 6.6 Hz, 3H), 1.58 (d, 1 = 11.0 Hz, 1H), 1.85 (dd, 1 = 10.3, 10.3 Hz, 1Η), 1.99 (dd, 1 = 11.4, 11.4 Hz, 1Η), 2 , 54-2.68 (m, 2Η), 2.75 (d, 1 = 11.4 Hz, 1H), 2.88 (broad s, 1H), 3.10 (dd, 1 = 9.1 , 14.8 Hz, 1H), 3.30 (dd, 1 = 9.1, 13.7 Hz, 1H), 3.52 (br s, 1H), 4.09 (sq.t, 1 = 7.0 Hz, 2H), 5.12 (sq.t, 1 = 9.12 Hz, 1H), 7.00-7.13 (m, 2H), 7.18 (d, 1 = 10.3 Hz, 1H), 7.30 (dd, 1 = 10.3, 10.3 Hz, 1H), 7.33-7.48 (m, 3H), 7.57 (dd, 1 = 9.5,

- 18 011439

9.5 Hz, 1H), 7.72 (d, 1 = 9.5 Hz, 1H), 7.87 (dd, 1 = 9.5, 9.5 Hz, 1H), 8.15 (d, 1 = 7.8 Hz, 1H) ppm; MS (E81 ⁺ ) t // = 653.3 [M + H] ⁺ . Elemental analysis: calculated C, 66.24%; H 6.18%; G 11.64%; N, 8.58%. Found: C, 66.17%; H 6.05%; N 8.56%; G 11.59%.

Examples 2-11

Table 1

Example X Η ¹ K ² 2 = m- -OSH2SE3 X ^ 5O ₂ E ( 3 = Ν- -based ₂ wed ₃ X ^ GodMe 4 = Ν- -OSN ₂ SR ₃ .4-0 5 = Ν- -OSN ₂ SR ₃ well 0 = Ν- -OE1 X> 5O ₂ P11 7 = Ν- • OE1 AO 8 = Ν- -OE1 F nine = Ν- -OE1 X> 5O ₂ E1 10 = CH- -OE1 ΧΧδ ^ Εί eleven = sn- -OSN ₂ SR ₃

Example 2

Scheme B

Β1 B2 2

Compound B1 is synthesized as described in International Publication No. HUO 02/83143 (Scheme 9, p. 91) using p-phenethidine instead of 4- (2,2,2-trifluoroethoxy) aniline in step 3. Compound 2 is synthesized from B1 in two stages, as shown in Scheme B.

(K) -2- [1 - (2-Ethanesulfonylethylamino) ethyl] -3- [4- (2,2,2-trifluoroethoxy) phenyl] -3H-pyrido [2,3-6]] pyrimidin-4-one (AT 2).

A mixture of 2.18 g of B1 (5.98 mmol, 1.00 eq.) And 687 μl of ethyl vinyl sulfone (6.58 mmol, 1.10 eq.) In 10 ml of methanol was stirred overnight in an oil bath at 50 ° C. then concentrated in vacuo. Product B2 is used in the next step without further purification. MS (E81 ⁺ ) t / ζ = 485.1 [M + H] ⁺ .

(K) -№ (2-Ethanesulfonylethyl) -2- (4-fluoro-3-trifluoromethylphenyl) -№ (1- {4-oxo-3- [4- (2,2,2-trifluoroethoxy) phenyl] -3 , 4-dihydropyrido [2,3-6] pyrimidin-2-yl} ethyl) acetamide (2).

(4-Fluoro-3-trifluoromethylphenyl) acetyl chloride is prepared by adding a few drops of DMF to a solution of 2.06 g of (4-fluoro-3-trifluoromethylphenyl) acetic acid (9.27 mmol, 1.70 equiv.) Cooled in an ice bath 0.81 ml of oxalyl chloride (9.27 mmol, 1.70 equiv.) In 15 ml of dichloromethane. After the start of gas evolution, the reaction mixture is allowed to spontaneously warm to room temperature and then it is stirred for 2 hours until gas evolution ceases. The resulting solution was added dropwise over a period of 15 minutes to a solution of 2.6 g of B2 (5.37 mmol, 1.00 equiv.) And 2.24 ml of triethylamine (16.1 mmol, 3.00 equiv.) In 20 ml of dichloromethane cooled in a bath with a mixture of acetone-dry ice. The resulting mixture was stirred at reduced temperature for 20 minutes, then poured into a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with saturated

- 19 011439 brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the product as a solid glassy substance. The product is purified by silica gel chromatography (elution with a gradient, from 50% ethyl acetate in hexane to 100% ethyl acetate). The product obtained after chromatography was recrystallized from methyl tert-butyl ether to give compound 2 as colorless crystals, mp = 157-159 ° C.

¹ H NMR (400 MHz; SES1 ₃ ; T = 300 K) (mixture of 8-cis: 8-trans-amide rotamers in a ratio of about 2.3: 1) δ 1.20 (t, 1 = 7.6 Hz, 3H), 1.46 (t, 1 = 7.2 Hz, 6.5H), 1.46 (d, 1 = 7.2 Hz, 6.5H), 2.48 (d, 1 = 16 Hz, 1H), 2.92 (ddd, 1 = 2.8, 7.6, 16.0 Hz, 2H), 2.94 (d, 1 = 16 Hz, 1H), 3.13 (ddd, 1 = 3 6, 7.2, 14.8 Hz, 4.6H), 3.22 (dd, 1 = 6.8, 6.8 Hz, 2H), 3.50 (ddd, 1 = 5.2, 10 6, 13.3 Hz, 2.3H), 3.67 (ddd, 1 = 8.0, 8.0, 13.3 Hz, 1H), 3.84 (s, 4.6H), 3, 90 (ddd, 1 = 4.8, 10, 14.8 Hz, 2.3H), 4.02 (ddd, 1 = 8.0, 8.0, 13.3 Hz, 1H), 4, 06- 4, 27 (m, 4.6H), 4.42 (qt, 1 = 8 Hz, 6.6H), 5.01 (qt, 1 = 6.8 Hz, 1H), 5.16 (sq.t, 1 = 7.2 Hz, 2.3H), 7.09-7.19 (m, 10H), 7.21-7.28 (m, 5H), 7, 33-7.50 (m, 8.9H), 7.53 (dd, 1 = 4.6, 9.1 Hz, 1H), 7.63-7.68, (m, 2.3H), 8.58 (dd, 1 = 2.0, 8.0 Hz, 2.3H), 8.61 (dd, 1 = 2.0, 8.0 Hz, 1H), 8.96 (dd, 1 = 2.0, 4, 4 Hz, 2.3H), 9.06 (dd , 1 = 2.0, 4.8 Hz, 1H) ppm. MS (E81 ⁺ ) t / ζ = 688.9 [M + H] ⁺ . Elemental analysis: Calculated: C 52.33%, H 3.95%; E 19.31%; N, 8.14% N.

Found: C 52.29%, H 3.97%; E 19.40%; N, 8.12%.

Example 3

Scheme C

B1 C1 3 (B) -2- (4-fluoro-3-trifayurmethylphenyl) -H- (2-methanesulfonylethyl) -H- (1- {4-oxo-3- [4- (2,2,2-trifluoroethoxy ) phenyl] -3,4-dihydropyrido [2,3-b] pyrimidin-2-yl} ethyl) acetamide (3).

Compound 3 is synthesized in two stages from B1 in accordance with the above synthesis sequence of compound 2, using ethyl vinyl sulfone instead of methyl vinyl sulfone in the first stage. ^: H NMR: a mixture of cis / trans-amide rotamers in a ratio of about 2.0: 1 (400 MHz; SES1 ₃ ; T = 298 K) δ ^ π ™ 8.98 (dd, 1 = 4, 46, 1, 78 Hz, 1H), 8.62 (dd, 7.69, 1, 78 Hz, 1H), 7.66 (dd, 1 = 9.71, 3.33 Hz, 1H), 7.10-7.46 (m, 7 N), 5.14 (q, 1 = 7.26 Hz, 1H), 4.41 (q, 1 = 7.94 Hz, 2 H), 3.64-4.24 (m , 5H), 3.10 (s, 3H), 2.47 (m, 1H), 1.46 (d, 1 = 7.2 Hz, 3H) and 5 _additional . 9.06 (m, 1H), 8.63 (fuzzy dd, 1 = 7.28, 1.63 Hz, 1H), 5.01 (q, 1 = 6.64 Hz, 1H), 2.83 ( s, 3H), 1.58 (d, 1 = 6.71 Hz, 3H) ppm. MS (E81 ⁺ ) 675 [M + H] ⁺ .

Examples 4 and 5.

Scheme Ό

ΝΗ,

IN 1

Compounds 4 and 5 are synthesized from B1 described above in two stages and three stages, respectively, as shown in Scheme Ό.

(B) -2- {1 - [(Tetrahydrothiopyran-4-ylmethyl) amino] ethyl} -3- [4- (2,2,2-trifluoroethoxy) phenyl] -3Npyrido [2,3-b] pyrimidin-4 -one (Ό1).

The above described B1 (159 mg, 0.44 mmol), tetrahydrothiopyranyl-4-carboxaldehyde (70 μl, 0.53 mmol) and sodium triacetoxyborohydride (277 mg, 1.32 mmol) are stirred in 1,2-dichloroethane at room temperature in for 1 h. The reaction mixture was diluted with dichloromethane, then washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 208 mg Ό 1, which was used without further purification.

- 20 011439 (Β) -2- (4-Fluoro-3-trifluoromethylphenyl) -N- (1- {4-oxo-3- [4- (2,2,2-trifluoroethoxy) phenyl] -3,4- dihydropyrido 12,3-ό. | pyrimidin-2-yl} ethyl) -H- (tetrahydrothiopyran-4-ylmethyl) acetamide (4).

4-Fluoro-3-trifluoromethylphenylacetic acid (164 mg, 0.74 mmol) is dissolved in dichloromethane and cooled to 0 ° C. Oxalyl chloride (64 μl, 0.74 mmol) was added, after 5 min, Ν, Ν dimethylformamide (5.7 μl, 0.07 mmol) was added. The reaction mixture was stirred at 0 ° C for 30 min and at room temperature for 1 h. The resulting solution was slowly added to a mixture of Ό1 (208 mg, 0.43 mmol) and triethylamine (182 μl, 1.30 mmol) in dichloromethane at -78 ° C. The mixture was stirred for 30 minutes, then washed with saturated aqueous sodium hydrogencarbonate and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting product was purified by chromatography (2% methanol and 0.1% ammonium hydroxide in dichloromethane) to give 265 mg of compound 4.

(Κ.) - N- (1,1-dioxohexahydro-1λ ⁶ -thiopyran-4-ylmethyl) -2- (4-fluoro-3-trifluoromethylphenyl) -N- (1- {4oxo-3- [4- ( 2,2,2-trifluoroethoxy) phenyl] -3,4-dihydropyrido [2,3-th] pyrimidin-2-yl} ethyl) acetamide (5).

Compound 4 (265 mg, 0.39 mmol) was dissolved in dichloromethane and cooled to 0 ° C. To the resulting solution was added 3-chloroxybenzoic acid (77%, 174 mg, 0.78 mmol) and the mixture was allowed to warm to room temperature overnight. The reaction mixture was washed twice with a 10% aqueous sodium thiosulfate solution and once with brine. Then the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography (3% methanol and 0.1% ammonium hydroxide in dichloromethane) to give 136 mg of compound 5.

MS (MH +): 688.2.

¹ H NMR (500 MHz; C!) Cb; T = 298 K): δ 8.30 (t, 1H, 1 = 7.9 Hz), 7.86 (m, 1H), 7.69-7.35 (m, 4H), 7.25 (m , 2H), 7.13 (m, 3H), 5.23-4.93 (dec., 1H, 1 = 7.2, 143 Hz), 4.43 (quint., 2H, 1 = 8.0 Hz), 4.22-3.58 (m, 2H), 3.26 (m, 1H), 3, 06-2, 97 (m, 3H), 1.55 (d, 2H, 1 = 6, 7 Hz), 1.43 (dt, 3H, 1 = 7.6, 2.0 Hz), 1.32 (t, 3H, 1 = 7.5 Hz) ppm.

Example 6

Scheme E

E1 6

The synthesis of compound E1 is described in International Publication No. XVO 02/83143 (Scheme 9, p. 91). Compound 6 is synthesized from E1 in two stages.

(Κ.) - N- (2-Benzenesulfonylethyl) -N- {1- [3- (4-ethoxyphenyl) -4-oxo-3,4-dihydropyrido [2,3-ά] pyrimidin-2-yl] ethyl } -2- (4-fluoro-3-trifluoromethylphenyl) acetamide (6).

Compound 6 is synthesized in two stages from compound E1 in accordance with the synthesis sequence of compound 2, but using ethyl vinyl sulfone instead of phenyl vinyl sulfone in step 1.

'H NMR: mixture of cis / trans-amide rotamers in a ratio of 2.0: 1 (400 MHz, SES1 ₃ ; T = 25 ° C) δ ^ π ™ 8.98 (dd, 1 = 4.63, 1.94 Hz, 1H), 8.61 (d, 1 = 7.97, 1.80 Hz, 1H), 7.98 (d, 1 = 7.43 Hz, 1H), 7.01-7.75 (m , 12H), 5.14 (q, 1 = 7.20 Hz, 1H), 4.07 (m, 2H), 2.86-3.90 (m, 6H), 1.45 (fuzzy, 1 = 6.93 Hz, 3H), 1.34 (d, 1 = 7.23 Hz, 3H) and 0 _additional . 9.09 (dd, 1 = 4.3, 1.84 Hz, 1H), 8.64 (dd, 1 = 7.88, 1.87 Hz, 1H), 1.54 (d, 1 = 6, 73 Hz, 3H), 1.44 (fuzzy t, 1 = 6.74 Hz, 3H).

MS (Ε8Ι ⁺ ) 683 [M + H] ⁺ .

- 21 011439

Examples 7 and 8.

Scheme P

Compounds 7 and 8 are synthesized in two and three stages, respectively, as described previously for E1.

(K) -3- (4-Ethoxyphenyl) -2- {1 - [(tetrahydrothiopyran-4-ylmethyl) amino] ethyl} -3H-pyrido [2,3-th] pyrimidin-4-one (P1).

To a mixture of E1 (531 mg, 1.71 mmol) and tetrahydrothiopyran-4-carbaldehyde (234 mg, 1.79 mmol) in 9 ml of 1,2-dichloroethane was added 1.09 g (5.13 mmol) of sodium triacetoxyborohydride at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After that, 25 ml of a saturated aqueous sodium hydrogen carbonate solution was added and the resulting mixture was extracted with dichloromethane (30 ml x 3). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dried in vacuo to give 550 mg of product P1, which was used in the next step without further purification. MS (E8C) 425 [M + H] ⁺ .

(K) -Y- {1- [3- (4-Ethoxyphenyl) -4-oxo-3,4-dihydropyrido [2,3-th] pyrimidin-2-yl] ethyl) -2- (4-fluoro- 3 trifluoromethylphenyl) -H- (tetrahydrothiopyran-4-ylmethyl) acetamide (7).

A mixture of P1 (550 mg, 1.29 mmol), 4-fluoro-3-trifluoromethylphenylacetic acid (374 mg, 1.68 mmol), EES (371 mg, 1.93 mmol), NOVT (198 mg, 1.29 mmol) ) and 300 μl (2.58 mmol) ΝΜΜ in 13 ml of dichloromethane are stirred at room temperature for 3 days. After this, the mixture was concentrated and 15 ml of water was added. The resulting mixture was extracted with ethyl acetate (30 ml x 3). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by column chromatography (silica gel, elution: ethyl acetate / hexane mixture, successively 50%, 80%) to obtain 531 mg of product 7.

¹ H NMR for a mixture of cis / trans amide rotamers in a ratio of approximately 2: 1 (400 MHz, SES1 ₃ : T = 25 ° C) 5 _basic 8.96 (dd, 1 = 4.58, 2.01 Hz, 1H ), 8.56 (dd, 1 = 7.87, 2.02 Hz, 1H), 7.0-7.55 (m, 8H), 5.16 (q, 1 = 7.21 Hz, 1H) 4.05 (q, 1 = 6.92 Hz, 2H), 1.44 (fuzzy d, 1 = 7.19 Hz, 3H), 1.43 (fuzzy t, 1 = 6.96 Hz, 3H ) and 8 _add . 9.06 (dd, 1 = 4.56, 1.96 Hz, 1H), 8.63 (dd, 1 = 7.90, 1.96 Hz, 1H), 5.02 (q, 1 = 6, 81 Hz, 1H), 1.58 (d, 1 = 6.74 Hz, 3H).

MS ⁺ ) 629 [M + H] ⁺ .

(K) -Y- (1,1-dioxohexahydro-1X ^6- thiopyran-4-ylmethyl) -H- {1- [3- (4-ethoxyphenyl) -4-oxo-3,4-dihydropyrido [2,3 -th] pyrimidin-2-yl] ethyl} -2- (4-fluoro-3-trifluoromethylphenyl) acetamide (8).

To a solution of compound 7 (531 mg, 0.845 mmol) in 8 ml of dichloromethane, 379 mg (1.69 mmol) of 3-chloroxybenzoic acid (77%) was slowly added. The resulting mixture was stirred at room temperature for 3 hours. After this, 30 ml of a saturated aqueous solution of sodium thiosulfate was added and the resulting mixture was extracted with dichloromethane (40 ml × 3). The combined extracts were washed with saturated aqueous sodium thiosulfate and water, dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by column chromatography (elution: ethyl acetate / hexane, successively 50 and 100%) to obtain 484 mg of compound 8.

'H NMR: mixture of cis / trans-amide rotamers in a ratio of about 4: 1 (400 MHz, SECD: T = 25 ° C) δ ......... _oh 3.60 (d, 1 = 3, 60 Hz, 1H), 8.85 (d, 1 = 6.64 Hz, 1H), 7.04-7.68 (m, 8H), 5.13 (q, 1 = 7.29 Hz, 1H) 4.10 (q, 1 = 6.97 Hz, 2H), 3.90 (ABy, 1 _AB = 16.3 Hz, 1H), 3.59-3.75 (m, 3H), 2.85 -3.17 (m, 4H), 1.80-2.35 (m, 5H), 1.46 (1 = 6.95 Hz, 3H), 1.43 (d, 1 = 7.43 Hz, 3H) and 5 _add . 9.10 (m, 1H), 8.78 (m, 1H), 1.59 (d, 1 = 6.74 Hz, 3H). MS (E8I ⁺ ) 661 [M + H] ⁺ .

- 22 011439

Example 9

Scheme O

E1 9 (Β) -N- (2-Ethanesulfonylethyl) -N- {1- [3- (4-ethoxyphenyl) -4-oxo-3,4-dihydropyrido [2,3-] pyrimidin2-yl] ethyl} - 2- (4-fluoro-3-trifluoromethylphenyl) acetamide (9).

Compound 9 is synthesized in two stages from E1 in accordance with the synthesis sequence of compound 2.

'H NMR of compound 9 (mixture of cis / trans-amide rotamers in a ratio of about 1.2: 1) (400 MHz, SES1 ₃ ; T = 25 ° C) 5 _basic 8.94 (dd, 1 = 4.60, 2 , 00 Hz, 1H), 8.58 (dd, 1 = 7.87, 1.99 Hz, 1H), 7.02-7.55 (m, 8H), 5.21 (m, 1H), 3 82-4.19 (m, 5H), 3.48 (m, 1H), 3.09-3.21 (m, 2H), 2.88-2.93 (m, 2H), 1.41 -1.47 (m, 9H) and 5 _additional . 9.05 (dd, 1 = 4.60, 2.02 Hz, 1H), 8.63 (dd, 1 = 7.89, 1.98 Hz, 1H), 5.05 (m, 1H), 3 66 (m, 1H), 2.43 (ABb, 1av = 16.3 Hz, 1H), 1.58 (d, 1 = 6.89 Hz, 3H), 1.22 (t, 1 = 7, 45 Hz, 3H). MS (ΕδΙ ⁺ ) 635 [M + H] ⁺ .

Example 10

Scheme H

A1 H1 10

The compound of example 10 is synthesized in two stages from the previously described compound A1. (Β) -2- [1- (2-Ethanesulfonylethylamino) ethyl] -3- (4-ethoxyphenyl) -3H-quinazolin-4-one (Η1).

A mixture of 0.2 g of compound A1 (0.647 mmol, 1.00 equiv.) And ethyl vinyl sulfone (0.809 mmol, 1.25 equiv.) In 5 ml of methanol was stirred at 70 ° C. for 5 hours, then the solution was concentrated in vacuo. The product is used in the next step without further purification. MS (ΕδΙ ⁺ ) 430.1 (MH ⁺ ).

(Β) -N- (2-Ethanesulfonylethyl) -N- {1- [3- (4-ethoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} -2 (4-fluoro-3 trifluoromethylphenyl) acetamide (10).

UES (18 4 mg, 0.96 mmol) is added to a mixture of compound Η1 (137 mg, 0.32 mmol), 4-fluoro-3 trifluoromethylphenylacetic acid (108 mg, 0.49 mmol), Η0Η1 (22 mg, 0.16 mmol) and ΝΜΜ (97 mg, 0.96 mmol) in 5 ml of DMF. The mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The solution was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography to give the product as a white solid (160 mg).

'H NMR (SIS1 ₃ ) (mixture of cis-trans-amide rotamers in a ratio of about 2.57: 1) 1.31 (t, 2.16H, 1 = 7.5 Hz), 1.46 (m, 4, 68H), 1.56 (d, 2.16H, 1 = 7 Hz), 2.5 (d, 0.72H, 1 = 16.5 Hz), 2.98 (m, 3H), 3.28 ( m, 1H), 3.55 (m, 0.28H), 3.72 (m, 1H), 3.82 (m, 0.56H), 3.95 (m, 0.72H), 4.11 (m, 2.72 N), 5.00 (q, 0.72 H, 1 = 7 Hz), 5.28 (q, 0.28 H, 1 = 7 Hz), 7.05 (m, 0, 72H), 7.16 (m, 5.28H), 7.29 (m, 1H), 7.49-7.61 (m, 2H), 7.80 (m, 0.28H), 7.86 (m, 0.72H), 8.31 (d, 1H, 1 = 7.5 Hz), MS (ΕδΙ ⁺ ) 634.1 (MH ⁺ ).

Example 11

Compound ΙΙ is synthesized in accordance with the procedure described in International Publication No. \ ¥ 0 02/83143 (Scheme 3, p. 77), with the difference that 4- (2,2,2-trifluoroethoxy) aniline is used instead of p-phenethidine in stage b. Compound 11 is synthesized from the above Ι 1 in two stages, as shown in scheme Ι.

(Β) -2- [1- (2-Ethanesulfonylethylamino) ethyl] -3- [4- (2,2,2trifluoroethoxy) phenyl] -3H-quinazolin-4-one (12).

- 23 011439

The above 11 (158 mg, 0.43 mmol) and ethyl vinyl sulfone (68 μl, 0.65 mmol) were dissolved in methanol and stirred at 60 ° C. for 3 hours. Methanol was removed in vacuo to give 210 mg of compound 12, which was used in the next synthesis step without further purification.

MS (Ε8Ι ⁺ ): ™ / ζ = 484.1 [M + H] ⁺ .

(K) -№ (2-Ethanesulfonylethyl) -2- (4-fluoro-3-trifluoromethylphenyl) -№ (1- {4-oxo-3- [4- (2,2,2-trifluoroethoxy) phenyl] -3 , 4-dihydroquinazolin-2-yl} ethyl) acetamide (11).

4-Fluoro-3-trifluoromethylphenylacetic acid (164 mg, 0.74 mmol) is dissolved in dichloromethane and cooled to 0 ° C. Oxalyl chloride (64 μl, 0.74 mmol) was added to the resulting mixture, and мин, Ν-dimethylformamide (5.7 μl, 0.07 mmol) was added after 5 minutes. The reaction mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 1 hour. The resulting solution was slowly added to a mixture of compound 12 (210 mg, 0.43 mmol) and triethylamine (182 μl, 1.30 mmol) in dichloromethane at -78 ° C. The resulting mixture was stirred for 30 minutes, then washed with saturated aqueous sodium hydrogen carbonate and brine. The mixture was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC to give 256 mg 11 as a colorless solid. MS (Ε8Ι +): u ^ = 715.2 [M + H] ⁺ .

'|| NMR (500 MHz; ATP1 ₃ ; T = 298 K): δ 9.10-8.95 (m, 1H), 8.66-8.58 (m, 1H), 7.78-7.57 (m , 1H), 7, 47-7, 36 (m, 3H), 7.24 (m, 1H), 7.13 (m, 3H), 5.03 (q, 1H, 1 = 7.4 Hz) 4.43 (quint. 2H, 1 = 8.0 Hz), 3.77 (s, 1H), 3.71 (m, 1H), 3, 62-3, 49 (m, 2H), 3 , 23-3, 09 (m, 3H), 2.81 (d, 1H, 1 = 12.9 Hz), 2.62-2.41 (m, 1H), 2.14-1.90 (m , 2H), 1.68 (broad s, 2H), 1.64-1.45 (m, 3H) ppm.

Examples 12-14.

table 2

Example A ⁴ to ¹ Me / 12 -Ν = -sn ₂ - -OE1 l'h Me Me thirteen = CH- -CH ₂ - -OE1 Me 14 = CH- missing -OEC XX ^s \ - / me

Examples 12-14.

Scheme 1

Me

Me

Me

Vg _{2 (} RRIZ

CH ₂ C1 ₂

Me

Me

Intermediate 13 is synthesized from commercially available L in two stages, as shown in Scheme 1.

2,5- (Dimethyl-2H-pyrazol-3-yl) methanol (12). A solution of lithium aluminum hydride (1.0 M in tetrahydrofuran, 1.7-8 ml) was added over 5 minutes at room temperature to a solution of commercially available ethyl 1,3-dimethyl-1H-pyrazole-5-carboxylate (L, 300 mg, 1 78 mmol) in tetrahydrofuran. The reaction mixture was stirred overnight. Then add water (67 μl), a 15% aqueous solution of sodium hydroxide (202 μl) and again water (67 μl). The resulting solid product is filtered off and dried in vacuo, then purified by chromatography (elution with a gradient: methanol to dichloromethane from 3 to 7%) to obtain 175 mg of 12 as a colorless solid.

5-Bromomethyl-1,3-dimethyl-1H-pyrazole (13).

Bromine (229 mg, 1.4-4 mmol) in dichloromethane was added to a solution of triphenylphosphine (376 mg, 1.44 mmol) in dichloromethane cooled in an ice water bath. The reaction mixture was stirred for 10 minutes, then compound 12 (170 mg, 1.34 mmol) was added in one portion, after which the solution was allowed to warm to room temperature for 2 hours. The reaction mixture was quenched with water, the aqueous layer was extracted with dichloromethane (2x25 ml ) The combined organic layer is washed

- 24 011439 sequentially with a 10% aqueous solution of sodium thiosulfate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (elution: 1: 1 hexane: ethyl acetate) to obtain 195 mg 13 as a colorless solid.

¹ H NMR (400 MHz; C1) SK T = 298 K): δ 6.07 ppm. (s, 1H), 4.44 (s, 2H), 3.83 (s, 3H), 2.23 (s, 3H) ppm.

Scheme K

Compound 12 is synthesized from compound E1 in two stages, as shown in Scheme K. Compounds E1, 13 and potassium carbonate are reacted in dimethylformamide, the product is purified to give compound K5. K5 is reacted with 4-fluoro-3-trifluoromethylphenylacetic acid and oxalyl chloride in triethylamine, dichloromethane and DMF. Compound 14 is filtered and concentrated.

Scheme E

SR ₃

B 13

Compound 13 is synthesized from the previously described compound E1 in four stages, as shown in Scheme E. E1 is reacted with methyl vinyl ketone and the resulting product is isolated to give compound L1. E1 is reacted with 4-fluoro-3-trifluoromethylphenylacetic acid and the resulting product is isolated to give compound E2. E2 is reacted with cyclobutylamine and sodium triacetoxyborohydride and the resulting product is isolated to give compound E3. E3 is reacted with formaldehyde and sodium triacetoxyborohydride, and the resulting product is isolated to give compound 13.

Compound 14 is synthesized from Compound E1 described above, as shown in Scheme M. Compound E1 is reacted with 1-isopropyl-4-piperidone and triacetoxyborohydride of sodium 25, after which the resulting product M1 is isolated. M1 is reacted with 4-fluoro-3-trifluoromethylphenylacetic acid and oxalyl chloride to isolate compound 14 as a product.

Example 15

Scheme Ν

(a) Ш, SWE, CH ₂ Cl ₂ , -25 ° C, 1.5 hours; (B) 2-aminonicotinic acid, CH ₂ Cl ₂ , -25 to 15 ° C, 12 hours; (c) 1) 4-iodaniline, CH ₂ Cl ₂ , -10 to 15 ° C, 12 hours; (b) Ш, SHSE, CH ₂ Cl ₂ , -25 ° C, 12 h (total yield 13%).

Compound 15 is synthesized from commercially available substances, as shown in scheme Ν. (K) -tert-Butyl-1 - (3- (4-iodophenyl) -4-oxo-3,4-dihydropyrido [2,3-b] pyrimidin-2-yl) ethyl carbamate (15).

A solution of Boc-b-alanine and compound Ν1 (10.0 g, 52.9 mmol) in CH ₂ Cl ₂ (140 ml) was cooled to -25 ° C (temperature of the reaction mixture). Ν-methylmorpholine (ΝΜΜ) (13.8 ml, 125 mmol) and isobutyl chloroformate (HBCE) (13.5 ml, 104 mmol) were successively added to the mixture at such a rate that the temperature of the reaction mixture remained below -25 ° C. After 1.5 hours, the mixture was transferred via cannula into a 250 ml three-necked flask equipped with a thermometer and containing dry 2-aminonicotinic acid (7.28 g, 52.7 mmol). After completion of the addition (about 10 minutes), the internal temperature of the mixture was brought to -10 ° C. The reaction mixture was allowed to warm for 17 hours with vigorous stirring to a temperature of 15 ° C. The mixture was cooled to 0 ° C and washed with ice-cold HCl (2x100 ml), brine (100 ml) and dried over No. 8O ₄ . The resulting solution 2 was loaded into a 250 ml three-necked flask, cooled to -25 ° C and treated with solid 4-iodaniline (11.61 g, 53 mmol). The resulting dark mixture was allowed to warm to 15 ° C and the mixture was stirred for 12 hours. The solution was washed! HC1 (2x100 ml), saturated NaHCO3 solution (2 X100 ml), brine (100 ml) and su Να28 ^ Γ ₄ . The mixture was cooled to -25 ° C and treated with ΝΜΜ (6.8 ml, 61.8 mmol), then CCE (6.7 ml, 56.1), keeping the temperature of the reaction mixture below -25 ° C. After stirring for 12 hours, the reaction mixture was washed with ΕΝ HCl (2x100 ml), saturated NaHCO3 solution (2x100 ml), saturated brine (100 ml), dried over NaBO ₄ and concentrated. Purification of the residue by column chromatography (column 50x400 mm, silica gel; elution with a gradient of acetone / CH ₂ Cl ₂ from 5 to 25%) affords compound 15 (3.41 g, 13%; purity 96% LIS). K _E = 0.37 (15% acetone / CH ₂ Cl ₂ ).

Example 16

Scheme O

EunVos ΝΗΒοο

16 (a) (P ₃ P) ₄ Pb, CuE Ν αϋΝ, MESC, 70 ° C, 30 min (89%).

(K) -1ret-Butyl-1- (3- (4-cyanophenyl) -4-oxo-3,4-dihydropyrido [2,3-b] pyrimidin-2-yl) ethyl carbamate (16).

Compound 15 (2.02 g, 4.10 mmol) obtained in accordance with the procedure described above is combined with (Pb ₃ P) ₄ Pb (439 mg, 0.38 mmol), Cu1 (157 mg, 0.82 mmol) and ΝαϋΝ (406 mg, 8.29 mmol) in a 25 ml pear-shaped flask equipped with a reflux condenser. The mixture was dried under high vacuum in a dry atmosphere of Ν ₂ three times. After this, acetonitrile (6 ml) was added, the resulting suspension was heated to 70 ° C and maintained at the indicated temperature for 30 min, after which TLC and HPLC analysis showed an almost complete consumption of compound 15. The mixture was diluted with ЕУАс (100 ml) and filtered through friable a layer of celite. The filtrate was washed with a saturated aqueous solution of No. 1HC'O ₃ (100 ml). The aqueous layer was extracted with additional EyAc (2x50 ml). The combined extracts were dried over # 8O ₄ and concentrated. Purification of the residue by column chromatography (50x400 mm column; silica gel; elution with a gradient of 80% EYAc / hexanes to 100% EYAc) yields Compound 16 (1.42 g, 89%; 96% AIS purity; 92% (chiral HPLC) )). KE = 0.35 (80% ENAc / Hexanes).

- 26 011439

Example 17

Scheme P

νη ₂

P1

(a) TFA, CH ₂ Cl ₂ (crude product yield 98%) (b) _ / ⁵ - ^Me MeOH, 50 ° C, 17 hours;

_P X ^ ^C ° ^{! H} (s) CP s ^{ 'EEC1, H0B1, ι-Ργ ₂ ΝΕ1, DMF, 17 h.

(K) -4- (2- (1-aminoethyl) -4-oxo-pyrido [2,3-th] pyrimidin-3 (4Н) -yl) beneonitrile (P1).

Compound 16 (1.05 g, 2.68 mmol), prepared as described above, was dissolved in CH ₂ Cl ₂ (40 ml) and treated with TFA (40 ml). The resulting mixture was stirred for 1.5 hours, then concentrated in vacuo. The concentrate was again dissolved in CH ₂ Cl ₂ (100 ml) and washed with saturated NaΗCO ₃ (100 ml).

The aqueous layers were extracted with additional portions of CH ₂ Cl ₂ (3x50 ml). The combined extracts were dried over No. ₂ 80 ₄ , concentrated and dried under high vacuum for 17 hours to give product P1 (767 mg, 98%), which was used further without further purification.

(K) -Y- (1- (3- (4-cyanophenyl) -4-oxo-3,4-dihydropyrido [2,3-th] pyrimidin-2-yl) ethyl) -H- (2- (ethylsulfonyl ) ethyl) -2- (4-fluoro-3- (trifluoromethyl) phenyl) acetamide (17).

Crude P1 (567 mg, 1.95 mmol) and ethyl vinyl sulfone (0.26 ml, 2.49 mmol) were combined in anhydrous MeOH (6.5 ml). The mixture was heated at 50 ° C (internal temperature) with stirring and held at this temperature for 17 hours, after which LC-MS analysis of the reaction mixture showed complete consumption of the starting material. The reaction mixture was partitioned between EJAc (100 ml) and water (50 ml). The ethyl acetate layer was washed with water (2x50 ml).

The combined wash layers were extracted with EJAc (2x50 ml). The combined extracts were dried over No. ₂ 804 and concentrated. The residue was combined with 4-fluoro-3-trifluoromethylphenylacetic acid (680 mg, 2.93 mmol), ΕΌΟ (2.98 mmol) and H0B1 (376 mg, 2.78 mmol) in DMF (5 ml). The resulting mixture was treated with Khanig base (Nishd'8 Lake) (1.35 ml, 7.75 mmol) and stirred at room temperature for 17 hours. The reaction mixture was diluted with EUAc (200 ml) and washed with 1Ν HCl (2x100 ml). The combined washings were extracted with ESAc (2x100 ml). The combined extracts were washed with saturated NaΗCO ₃ (200 ml), water (3x100 ml) and brine (100 ml), then dried over No. 80 ₄ and concentrated. The residue was purified by chromatography (silica gel; elution with a gradient of THF / CH ₂ Cl ₂ from 10 to 20%, then up to 100% THF) to obtain 17 (780 mg, 1.27 mmol, 65%) as a white amorphous solid (purity> 97% AIS at 254 nM). K _£ 0.2 (15% THF / CH ₂ Cl ₂ ). E8C shows a single endothermic transition at 179 ° C. MS (E8I ⁺ ) 616.6 (MH ⁺ ).

- 27 011439

Example 18

Compound 18 is synthesized from commercially available starting materials in four stages, as shown in Scheme O.

Benzyl ester (K) - {2-tert-butoxycarbonylamino-1- [3- (4-ethoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] ethyl} carbamic acid (01).

To a solution of anthranilic acid (1.86 g, 13.59 mmol) and K-2-benzyloxycarbonylamino-3-tert-butoxycarbonylaminopropionic acid (4.6 g, 13.59 mmol) in 25 ml of anhydrous pyridine was added triphenylphosphite (8.43 g, 27.18 mmol) at room temperature. The resulting solution was stirred at 60 ° C for 15 hours. P-phenetidine (1.86 g, 13.59 mmol) was added via syringe. The reaction mixture was stirred for an additional 3 hours at 60 ° C, cooled to room temperature and evaporated in vacuo to remove most of the pyridine. The residue in the form of a solution in ether was washed sequentially with 1Ν HCl, 1Ν NO. water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to a brown dry residue, which was purified by chromatography to give compound 01 as a white solid (4.48 g). MS (Ε8Ι ⁺ ) 559.2 (MH ⁺ ).

(K) tert-butyl ether - {2-amino-2- [3- (4-ethoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2yl] ethyl} carbamic acid (02).

To a solution of 01 (1 g, 1.79 mmol) and cyclohexa-1,3-diene (2.87 g, 35.84 mmol) in 30 ml of ethanol was added 10% palladium on activated carbon (0.19 g, 0, 18 mmol). The resulting solution was refluxed for 3 hours. The mixture was filtered and evaporated in vacuo to give the product as a white solid (0.53 g).

Ή NMR (SBS1 ₃ ) 1.35 (s, 9H), 1.48 (t, 3H, 1 = 7 Hz), 3.42 (m, 2H), 3.80 (s, 1H), 4.11 (q, 2H, 1 = 7 Hz), 5.09 (m, 1H), 7.06 (m, 2H), 7.22 (d, 1H, 1 = 8.5 Hz), 7.29 (m , 1H), 7.50 (t, 1H, 1 = 7.5 Hz), 7.72 (m, 1H), 7.79 (m, 1H), 8.30 (d, 1H, 1 = 8, 0 Hz) ppm MS (Ε8Ι ⁺ ) 425.2 (MH ⁺ ).

(K) tert-butyl ether - {2- [3- (4-ethoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] -2 - [(pyridin-3ylmethyl) amino] ethyl} carbamic acid ( eighteen).

Pyridine-3-carbaldehyde (0.13 g, 1.2 mmol) was added to a solution of compound 02 (0.44 g, 1 mmol) in dichloroethane (10 ml) at -10 ° C followed by sodium triacetoxyborohydride (0.32 g, 1.5 mmol). The mixture was kept at this temperature for 1.5 hours, then allowed to warm to room temperature and stirred overnight. The solution was diluted with dichloromethane, washed with saturated aqueous sodium hydrogencarbonate, water, saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give compound 18 as a yellow solid (0.50 g). MS (Ε8Ι ⁺ ) 516.2 (MH ⁺ ).

Examples 19-21.

- 28 011439

Example 19

(K) -3- (4-Ethoxyphenyl) -2- [2- (4-fluoro-3-trifluoromethylbenzyl) -3-pyridin-3-ylmethyl-4,5-dihydro-3Nimidazol-4-yl] -3H- quinazolin-4-one (19).

Trifluoroacetic acid (0.38 g, 3.34 mmol) was added to a solution of compound 15 (0.12 g, 0.167 mmol) in dichloroethane (3 ml). The mixture was heated to 60 ° C and kept at that temperature for 1.5 hours. The solvent was evaporated, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate, water, saturated brine and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by column chromatography to give the product as a white solid (67 mg).

¹ H NMR (SBSl) 1.49 (t, 3H, 1 = 6.96 Hz), 3.89-4.12 (m, 6H), 4.33 (m, 1H), 4.53 (m, 2H), 6.48 (m, 1H), 6.84 (m, 1H), 7.06 (m, 2H), 7.24-7.36 (m, 4H), 7.57 (m, 1H ), 7.68 (m, 1H), 7.80-7.90 (m, 2H), 8.33-8.34 (m, 2H), 8.86 (m, 1H). MS (ENG) 602.2 (MH ⁺ ).

Example 20

- 29 011439

Compound 20 is synthesized from commercially available starting materials in five steps, as shown in Scheme T.

4-tert-Butyl ether 1-benzyl ether (K) -2- [3- (4-ethoxyphenyl) -4-oxo-3,4-dihydroquinazolin2-yl] piperazine-1,4-dicarboxylic acid (T1). To a solution of anthranilic acid (1.91 g, 13.96 mmol) and 1-benzyl ester of 4-tert-butyl ether of piperazine-1,2,4-tricarboxylic acid (5.08 g, 13.96 mmol) in 25 ml of anhydrous pyridine triphenylphosphite (8.66 g, 27.92 mmol) was added at room temperature. The resulting solution was stirred at 70 ° C. for 15 hours. P-phenetidine (1.91 g, 13.96 mmol) was added via syringe. The reaction mixture was stirred for another 3 hours at 60 ° C, cooled to room temperature and evaporated in vacuo to remove most of the pyridine. The residue in ether is washed sequentially with an aqueous 1Ν hydrochloric acid solution, an aqueous 1 натрия sodium hydroxide solution, water and brine.

The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to a brown residue, which was purified by chromatography to give the product as a white solid (2.7 g). MS ^ ⁺ ) 585.2 (MH ⁺ ).

(K) -3 - [3 - (4-ethoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] piperazine-1-carbolic acid tert-butyl ester (T2). To a solution of compound T1 (2.5 g, 4.28 mmol) and cyclohexa-1,3-diene (6.85 g, 85, 62 mmol) in 60 ml of ethanol was added 10% palladium on activated carbon (0.45 g 0.43 mmol). The resulting solution was refluxed for 3 hours. The mixture was filtered and evaporated in vacuo to give the product as a white solid (1.85 g).

Ή NMR (SBS1Z) 1.43 (s, 9H), 1.49 (t, 3H, 1 = 7 Hz), 2.70 (m, 1H), 2.85 (br., 1H), 2.98 (m, 1H), 3.15 (d, 1H, 1 = 8 Hz), 3.59 (d, 1H, 1 = 8 Hz), 3.95 (br., 1H), 4.13 (m, 3H), 7.08 (m, 2H), 7.24-7.33 (m, 2H), 7.52 (m, 1H), 7.76 (m, 2H), 8.30 (d, 1H , 1 = 7.5 Hz). MS ^ ⁺ ) 451.2 (MH ⁺ ).

(K) -3- [3- (4-ethoxyphenyl) -4-oxo-3,4-dihydroquinazolin-2-yl] -4 - [(4-fluoro-3trifluoromethylphenyl) acetyl] piperazin-1 - tert-butyl ether carboxylic acid (TK). UES (1.53 g, 8.01 mmol) was added to the mixture of compound T2 (1.2 g, 2.67 mmol), 4-fluoro-3-trifluoromethylphenylacetic acid (0.71 g, 3.20 mmol), NOV ! (0.18 g, 1.34 mmol) and ΝΜΜ (0.81 g, 8.01 mmol) in 15 ml of DMF. The resulting mixture was stirred at room temperature overnight and then diluted with ethyl acetate. The resulting solution was washed with saturated aqueous sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography to give the product as a white solid (1.44 g).

Ή NMR (СОС1 ₃ ) 1.08 (s, 9Н), 1.47 (t, 3Н, 1 = 7 Hz), 3.05 (m, 2Н), 3.67 (m, 1Н), 3.81 (m, 2H), 4.10 (m, 3H), 4.24 (m, 1H), 4.49 (m, 1H), 5.19 (m, 1H), 7.11 (m, 3H) , 7.29 (m, 1H), 7.51 (m, 5H), 7.75 (m, 1H), 8.30 (d, 1H, 1 = 7.65 Hz) MS ^ ⁺ ) 655.2 (MH ⁺ ).

(K) -3- (4-Ethoxyphenyl) -2- {1 - [(4-fluoro-3-trifluoromethylphenyl) acetyl] piperazin-2-yl} -3Hquinazolin-4-one (20).

Trifluoroacetic acid (5.7 g, 50.15 mmol) was added to a solution of compound T3 (1.64 g, 2.51 mmol) in dichloromethane (90 ml). The resulting mixture was stirred at room temperature for 3 hours. The solvent was evaporated, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water, saturated brine and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by flash column chromatography to give the product as a white solid (1.28 g).

Ή NMR (СОС1 ₃ ) 1.42 (t, 3Н, 1 = 7.04 Hz), 2, 69-2, 79 (m, 2Н), 3.15 (m, 2Н), 3.58 (m, 1H), 3.72 (m, 2H), 4.04 (q, 2H, 1 = 7.04 Hz), 4.20 (m, 1H), 5.14 (m, 1H), 6.97- 7.15 (m, 4H), 7.34-7.50 (m, 5H), 7.72 (m, 1H), 8.24 (d, 1H, 1 = 7.76 Hz). MS (EZG) 555.1 (MH ⁺ ).

Example 21

21 (K) -3- (4-Ethoxyphenyl) -2- {1 - [(4-fluoro-3-trifluoromethylphenyl) acetyl] -4-methylpiperazin-2-yl} -3Hquinazolin-4-one (21).

Formaldehyde (37% in water) (0.015 g, 0.18 mmol) at room temperature was added to a solution of compound 20 (0.05 g, 0.09 mmol) in dichloroethane (5 ml), followed by addition of No. 1 (OAC) ₃ VN (0.057 g, 0.27 mmol). The mixture was stirred overnight. The resulting solution was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, water, brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by flash column chromatography to give the product as a white solid (40 mg).

- 30 011439 '|| NMR (SBS1 ₃ ) 1.42 (t, 3H, 1 = 7.0 Hz), 2.01-2.26 (m, 4H), 2.89 (m, 2H), 3.77 (m, 4H) ), 4.04 (q, 2H, 1 = 7.0 Hz), 4.46 (m, 1H), 5.41 (m, 1H), 7.01 (m, 3H), 7.06 (m , 1H), 7.41 (m, 5H), 7.71 (m, 1H), 8.21 (d, 1H, 1 = 8.08 Hz). MS (Ε8Ι ⁺ ) 569.2 (MH ⁺ ).

Examples 22-52

The compounds of Examples 22-52 are prepared in accordance with the synthesis methods described above and the synthesis schemes shown in FIG. 1, 4, 13, 14 and 16-18 in the International Publication VΟ 02/083143, with their application with minor modifications.

Table 1

Example Formula Characteristic (mass, MS + 1) 22 about SM ha! 630.6 23 2 ^{si Gy1} R 616.6

Example Formula Characteristic (mass, MS + 1) 24 p CCU ^ ^p_ g ^p 616.6 25 ° * ³¹ (X ' 666.6 26 o ^СЬга1 СУу · 616.6 27 Cb! Ha1 (UG r w xg γ * 616.6 28 SNG! H rpc ' 616.6 29th SK1ga1 Sire. " 614.6 thirty CIS # d # E 584.6

- 31 011439

Example Formula Characteristic (mass, MS + 1) 31 SR ₃ 584.5 32 -l ^ Snga! _p L ^ 0 rf? 566.6 33 ίί ^{SHIGA |} OAU ^sn · ΧΠΤΧ A ^r 593.6 34 X £ ^ γ ^ΞΝ0Νί91 596.6 35 αΑΤ “ΰΆ r'T'r 612.7 36 ⁰ NG ™ * SAAusch FA g o 628.6 37 / • А ^{С, 1} ' ^ha1 χήΑΑ ρ ^ ΓΈ Г 644.7

- 32 011439

Example Formula Characteristic (mass, MS + 1) 38 SM '"1 Si “ 598.6 39 Sya1 _r AE o »'b _μ > Αρ 630.6 40 ϋ | * ^{? W} | [ ^X “ ^YO '' ^{ha |} 610.6 41 With ¹ ' ³ ' kA _and A ^, CH _1X ^ / ΓΥΎ ^ ⁰ _Ρ > γ о г> 642.6 42 gt 598.6 43 SGI1M r / W ΕΑ _Ν 4γΟ5 arcES ¹ 615.6 44 ⁰ W / ⁵ rLr 595.6

- 33 011439

Example Formula Characteristic (mass, MS + 1) 45 609.7 46 641.7 47 629.6 48 ΐ * YAP 643.7 49 α · ιΐ Οόγ ™ · ' 598.6 fifty SMM> 644.7 51 Spa .лГГТ'ES ' G 1 615.6 52 HER 614.6

The study of SCHSC binding and migration

Study of SCX3 binding.

The following examples illustrate a CXC3 binding assay that can be used to evaluate a compound of the present invention as described in Example 12 of International Publication No. UO 02/083143.

Except where otherwise indicated, all reagents used in the analysis are available from commercial sources (for example, 81dta-A16psy, 81. Bosch, MO, I8A). Test compounds are diluted in DMSO to give a concentration that is 40 times the estimated final concentration of the assay; 5 μl of the resulting solution is transferred to each well of a 96-well flat-bottomed polyprolene microplate (e.g., from Steshet, 1 ps). Cells expressing CXSC3 (see International Publication No. UO 02/083143) are suspended in an experimental buffer (25 mM Nerez, 80 mM No. C1, 1 mM CaCl ₂ , 5 mM MDCl ₁ , 0.2% bovine serum albumin, pH 7 , 1, 4 ° C) at a concentration of 5 million cells per ml; 100 μl of the resulting cell suspension was transferred to each well of a 96 well plate containing diluted test compounds. A chemokine labeled with ¹²⁵ Ι (from commercial suppliers, for example, Atetzbat, PE Yke 8c1epsez) is diluted with ordinary buffer to a concentration of approximately 60 mM; 100 μl of the resulting chemokine solution is transferred to each well of a 96-well plate containing the compounds and the cell suspension. Tablets may be sealed by commercially available sealed foil lids (e.g., from E & K 8s1ep11Ps)

- 34 011439 and be stored at 4 ° C for a period of 2 to 4 hours with gentle shaking. At the end of this incubation period, the contents of the experimental microplates are transferred to CE / B filter plates (Raskagb), which were previously coated by immersion in a solution containing 0.3% polyethyleneimine (81dsh), using a cell harvester (Raskagb) and can be washed twice with wash buffer (25 mM Nerek, 500 mM NaCl, 1 mM CaCl ₂ , 5 mM MDCl ₂ , pH 7.1, stored at room temperature). Filter plates are hermetically sealed at the bottom with hermetic covers (Raskagb), 50 μl of scintillation solution Μίοτοκοίηΐ-20 (Raskagb) are added to each well and the plates are hermetically closed with transparent plastic on top (Tor8ea1 A, Raskagb). Tablets are counted on a scintillation counter such as Raskagb TorSoip !. To quantify nonspecific binding, 4 wells containing unlabeled “cold” chemokine can be placed on each 96-well microplate. To quantify the maximum binding, 4 wells containing 5 μl DMSO, 100 μl cell suspension and 100 μl ¹²⁵ 1-labeled chemokine solution can be isolated in each 96-well plate. The data can be analyzed using commercially available software (for example, Exce1 from Рοτοκοίΐ, Ргйт from СгарНРаб 8th ^ 1пс.).

Study of plasma migration CXCK3

The following example is a study of plasma migration of CXCK.3, which can be used to evaluate the activity of a compound of the present invention.

Mononuclear human peripheral blood cells (Nitap reyrega1 b1ob topoproteag s11k PBMC) are activated using OCT3 (purified by using AB solution from the cell line of hybridoma OKT3 (ATCC CB-8001)) and 1b-2 (Roergo! EsN, 1ps., Wax H111, N1, I8A), and after 14 days, chloromethylfluorescein diacetate (SMEEA) (Mo1ci1ag PrgoBec, 1 ps) was loaded into the cells by incubating the activated PBMCs in 1 ng / ml SMEEA for> 1.5 h at 37 ° C in a cell culture incubator. During cell loading, test compounds can be diluted with DMSO to a concentration that is 100 times the estimated final concentration of the study. Then, 100 ng / ml 1TAC of a person (RoGo! EsN) is prepared in human blood plasma (EITA, does not contain drugs, B1o1od | ca1 8res1a11u Co.). Test compounds are added to human 1TAC. Cells are washed once with pre-heated (37 ° C) BPM1 (1 Puitodep) medium with 0.5% B8A and resuspended in human plasma to a concentration of 5 million cells / ml. The test compound is added to PBMC. A 96-well microplate chemotaxis migration plate (NITROGOE, 1 ps) is prepared by adding 30 μl / well of a 1TAC / compound mixture to the lower chamber of the wells, placing an impermeable membrane on top of a 1TAC / compound mixture and adding 50 μl / well of PBMC / compound to each well . The microplates are closed and they can be stored in a tissue culture incubator with moisturization for 2.5 hours. A standard “CMEA loaded cell” curve can be obtained for use as a reference for experimental plates. Migration plates are disassembled and read in a fluorometric plate reader configured to absorb at 475 nm and emission at 517 nm. Fluorescence readings can be converted to the number of cells using a standard curve and counting the number of migrating cells as a percentage.

Other studies can be used to identify compounds that modulate the activity of CXCB3 chemokine receptors, for example, binding studies (see, for example, \\ 'ep e! A1. (1998) 1. Vu1. SN. 273: 18288-18291, Satbе11 e ! a1. (1998) 1. Ce11 Vu1. 141: 1053-1059, Epbgeck e! a1. (1999) 1. Exp. Furniture. 189: 1993-1998; Ν§ e! a1. (1999) 1. Meb. Ref. 42: 4680-4694), a study of the outflow of calcium (see, for example, ^ apde e! A1. (2000) Mo1. PHAGt. 57: 1190-1198; K.aa e! A1. (1999) 1ttypo1. 162: 3840-3850) and chemotaxis studies (see, for example, A1bape§1 e! A1. (2000) 1. 1tipo1. 165: 13951402; Loeisieg e! A1. (1998) Eig. 1. 1tipo1 28: 3696-3705), and t kzhe other ways assays known to those skilled in the art.

All publications, patents and patent applications mentioned in this description are incorporated into the description by reference as if each individual publication or patent application were specifically and individually indicated as entered by reference. Although the invention presented above has been described in some detail by way of illustration and examples for ease of understanding, it will be understood by one of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made without highlighting them from the scope and scope of the appended claims. inventions.

Claims (39)

CLAIM 1. The compound of formula (I) - 35 011439 I or a pharmaceutically acceptable salt or prodrug thereof, wherein A ¹ is CH and A ⁴ are CH or Ν; O is a bond, —OC (O) - and —CH ₂ CO; B represents (CH ₂ ) _m , where the subscript m is 0, 1 or 2; X represents —C (O) -; K ¹ is substituted phenyl, wherein the substituent is selected from the group consisting of —OE1, —OCH ₂ CE ₃ , —ΌΝ, and I; K ² represents —CH ₃ , CH ^ HBoc, or, optionally, K ² together with b and K ³ can form a 5- or 6-membered ring containing two nitrogen atoms; K ^{3 is} selected from the group consisting of —H, —8O ₂ CH ₃ , —8O ₂ CH ₂ CH ₃ , —CH ₂ 8O ₂ CH ₂ CH ₃ , —CH ₂ 8O ₂ CH ₃ , —C (CH ₃ ) ₃ , -CH- (OCH ₃ ) 2, CH (CH ₃ ) 2§O2CH2CH ₃ , -CH (CH ₃ ) 2§CH2CH ₃ , -8-CH (CH ₃ ) 2, 8O2CH (CH ₃ ) 2, -8O2C (CH ₃ ) ₃ , -CH (CH ₂ OCH ₃ ) 2, or, optionally, K ³ together with K ² can form a 5- or 6-membered ring containing two nitrogen atoms; K ⁴ is tert-butyl or substituted phenyl, where the substituents are selected from the group consisting of E, —CE ₃ and OSE ₃ ; 2. The compound according to claim 1, where K ³ selected from the group including -H, -8O ₂ CH ₃ , -8O ₂ CH ₂ CH ₃ , 3. The compound according to claim 1 of formula (1a) or a pharmaceutically acceptable salt or prodrug thereof. 4. The compound according to claim 1 or 3, where A ⁴ represents Ν. 5. The compound according to claim 1 or 3, where A ⁴ represents CH. 6. The compound according to claim 1 or 3, where K ¹ is para-substituted phenyl, where the substituent is selected from the group consisting of OE1, -OCH ₂ CE ₃ , CN and I. 7. The compound according to claim 1 or 3, where K ² represents-CH ₃ . 8. The compound according to claim 1 or 3, where O represents —CH ₂ C (O) -. 9. The compound according to claim 1 or 3, where b is a bond, —CH ₂ - or —CH ₂ CH ₂ -. 10. The compound according to claim 1 or 3, where b-K ³ together represent 11. The compound according to claim 1 or 3, where 0-K ⁴ represents 12. The compound according to claim 1 or 3, where K ¹ represents paracyanophenyl. 13. The compound according to claim 1 or 3 of the formula (II) - 36 011439 II or a pharmaceutically acceptable salt or prodrug thereof, where R ¹¹ represents-CH ₂ CH ₃ or -CH ₂ SR _3. r z ΎΊ 14. Connection by and. 13, where I represents methyl and -K represents 15. The compound according to item 13 or 14, where K ^{3 is} selected from the group consisting of -§O ₂ CH ₃ , -§O ₂ CH ₂ CH ₃ , 16. The compound according to item 13 or 14, where -P-K ⁴ represents 17. The compound according to clause 16, where K ³ selected from the group including -§O ₂ CH ₃ , -§O ₂ CH ₂ CH ₃ , 18. The compound of formula (ΙΙΙ) III or a pharmaceutically acceptable salt or prodrug thereof, wherein A ¹ is CH and A ⁴ are CH or Ν; O is a bond and —CH ₂ CO—; V and Υ each independently represents a carbon atom or a heteroatom, and V and Υ are joined together to form a 5- or 6-membered cycloheteroalkyl ring, wherein the 5- or 6-membered ring is unsubstituted or is substituted with methyl; X represents —C (O) -; K ¹ is substituted phenyl, wherein the substituent is selected from the group consisting of —OE !, —OCH ₂ CP ₃ , —ΟΝ, and Ι; K ^{3 is} selected from the group consisting of —H, K ⁴ is substituted phenyl, wherein the substituent is selected from the group consisting of P, CP3, and OCP3. 19. The compound of claim 18, wherein A ¹ is CH. 20. The compound of claim 18, wherein A ⁴ is Ν. 21. The compound of claim 18, wherein K ¹ is paracyanophenyl. 22. The compound of formula (ΙΥ) K ⁹ IV or a pharmaceutically acceptable salt or prodrug thereof, wherein XV ^{1 is} absent or is —CH ₂ -; V ² and Υ independently represent -CH ₂ -, -CH =, -ΝΉ-, Ν (ί.Ή ₃ ) - or -Ν =; V ^{3 is} absent or is —CH ₂ - or —Ν =; A ¹ represents CH and A ⁴ represent CH or Ν; - 37 011439 O is a bond and —CH ₂ CO—; X represents —C (O) -; B ¹ is substituted phenyl, wherein the substituent is selected from the group consisting of —OE1, OCH ₂ CE ₃ , —ΌΝ, and I; B ⁴ is substituted phenyl, wherein the substituent is selected from the group consisting of E, —CE ₃ and OSE ₃ . 23. The compound of claim 22, wherein A ¹ is CH. 24. The compound of claim 23, wherein A ⁴ is Ν. 25. The compound of claim 23, wherein A ⁴ is CH. 26. The compound of claim 25, wherein B ¹ is para-substituted phenyl, wherein the substituent is selected from the group consisting of —OE1, —OCH ₂ CE ₃ , —ΟΝ, and I. 27. The compound according A.25, where In ¹ represents ^ SNgSrz 28. The compound of claim 25, wherein B is paracyanophenyl. 29. The compound of claim 25, wherein O is —CH ₂ C (O) -. 30. The compound of claim 25, wherein —O — B ′ ¹ is 31. The compound of claim 25, wherein A ¹ is —CH ₂ -. 32. The compound of claim 25 or 31, wherein A ² is —Ν =, —ΝΗ— or —Y (CH ₃ ) -. 33. The compound according A.25, where A ¹ , A ³ and Υ each represents-CH ₂ -. 34. The compound of claim 25, wherein A ¹ is —CH ₂ -, A ² is —Ν =, A ^{3 is} absent, and Υ is —CH =. 35. The compound according to clause 34, where A ² represents -Y (CH ₃ ) - or -Ν4-. 36. The compound of claim 35, wherein —O — B ⁴ is 37. The compound of claim 36 wherein A ⁴ is —CH—. 38. The compound according to claim 1, where the compound is selected from the group including 39. A pharmaceutical composition comprising a compound according to claim 1 or 18 and a pharmaceutically acceptable carrier, diluent or excipient. - 38 011439 INSg MNSg a. ΝΜΜ, 0Η ₂ α _ζ , -20 “s, 12 hours; b. CH ₂ Cl ₂ , -20 “C, 4 hours; c. ΝΜΜ, sn ₂ C1 ₂ , -20 ”s, 2 hours; th. Pb catalyst on coal, 1,3-cyclohexadiene, CJS, room temperature. FIG. one a. κΐ, K ₂ СО _Э , DMF, room temperature - 80 ° С; b. ΝΜΜ, EOS. NOVT. DMF, room temperature; c. TFU, СН ₂ С1 ₂ , 0 ° С - room temperature; ΰ. K !, K ₂ CO ₃ , DMF, room temperature - 80 ° C; e. No. (ОАс) ₃ int, DChE, о ° С - room temperature. FIG. 2 - 39 011439 a. No. (OAc) ₃ int. DCE, 0 “s - room temperature; b. ΝΜΜ, EOS, novt, DMF, room temperature; c. TFU, СН ₂ С1 ₂ , 0 ° С - room temperature. FIG. 3